f^m Idl ffOf 'Si'Oira.c-t. Cornell University Library RB 131.A42 1909 lnflammation:an introduction *<> the j5t"d 3 1924 003 313 503 LIBRARY NEW YORK STATE VETERINARY COLLEGE ITHACA, NEW YORK /^^^\i m ^^^^^F ^^^^^^ , iiiimnmniiBuiniiiiiiiiiTnniiPiiiwiiir Digitized by Microsoft® This book was digitized by Microsoft Corporation in cooperation with Corneii University Libraries, 2007. You may use and print this copy in iimited quantity for your personai purposes, but may not distribute or provide access to it (or modified or partiai versions of it) for revenue-generating or other commerciai purposes. Digitized by Microsoft® Cornell University Library The original of tliis book is in tine Cornell University Library. There are no known copyright restrictions in the United States on the use of the text. http://www.archive.Qrg/details/cu31924003313503 '^ Digitized by Microsoft® Digitized by Microsoft® Digitized by Microsoft® INFLAMMATION Digitized by Microsoft® MACMILLAN AND CO., Limited LONDON . BOMBAY • CALCUTTA MELBOURNE THE MACMILLAN COMPANY NEW YORK . BOSTON ■ CHICAGO ATLANTA ■ SAN FRANCISCO THE MACMILLAN CO. OF CANADA, Ltd. TORONTO Digitized by Microsoft® INFLAMMATION AN INTRODUCTION TO THE STUDY OF PATHOLOGY BEING THE REPRINT (REVISED AND ENLARGED) OF AN ARTICLE IN PROFESSOR ALLBUTT'S 'SYSTEM OF MEDICINE' BY J. GEOEGE ADAMI, M.A, M.D., F.E.S. SOMETIME FELLOW OF JESUS COLLEGE, CAMBRIDGE PROFESSOB OF PATHOLOGY, m'GILL UNIVERSITY, MONTREAL MxiCMILLAN AND CO., LIMITED ST. MARTIN'S STREET, LONDON 1909 Digitized by Mtcfosoft® Mifro I'zrst Edition, AUlmtt's ''System of Medicine " Vol. I., 1896. Second Edition, ,, „ ,, ,, 1905. TJiird Edition^ Jatiuary 1907. Eourtk Edition, 1909. ,; u)ovn^*''^'^^^"■■ Digitized by Microsoft® PEEFACE TO FOURTH EDITION In preparing a further edition of this little book I have taken the opportunity to thoroughly revise it, and to amplify wherever it seemed that the somewhat con- densed nature of the treatment had made the meaning not perfectly clear. The additions of primary import- ance to which attention may be called are Opie's valuable observations upon the enzymes and anti-enzyme of inflammatory exudates, the work of Bail and others upon bacterial aggressions, and a discussion of the physics of the chemiotactic process as worked out more particularly by Ehumbler and Brailsford Eobertson. Attention is also drawn to Beattie and Dixon's obser- vation regarding the primary and secondary new capillaries of granulation tissue, and to Carrel's observa- tions upon the result of interposing a length of healthy vein in the course of an artery as confirming the author's views regarding the existence of a functional or strain- hypertrophy of connective tissue as distinct from an inflammatory overgrowth of the same. J. G. A. MoNTKEAL, J'u,ne 1909. Digitized by Microsoft® Digitized by Microsoft® PEEFACE TO THIRD EDITION The development of a science resembles strikingly that of the individual intelligence. Your child, once he begins to perceive, passes into the stage of perpetual " why ? " He is not satisfied with the recognition of phenomena, but would know from his elders how they come about. It is deserving of note that at first those explanations satisfy him that appeal to the imagination rather than to the reason. He is not prepared to appre- ciate and to accept mathematical proof; he lives in fairyland. Gradually his powers of reasoning become developed, but this under the guidance of his elders and teachers, and for long, while still seeking explanations, he accepts those given to him. There are those who never pass beyond this stage of deference to ' authority. But some, at least, as manhood approaches, begin to think for themselves ; begin to see that the explanations given by their elders are not all of them adequate, nor all satis- factory ; and so is reached the stage of youthful Sturm und Drang, during which period the brighter spirits, heedless of authority, in the exuberance of youthful imagination, proceed impatiently to weave and elaborate explanations of their own. It may be that, despite their little experience and the fewness of the facts on Digitized by Microsoft® viii INFLAMMATION which they base themselves, they light upon truths of wide scope. But too often it happens at this period that inadequate hypotheses are light-heartedly imagined and given to the world. During this period hypothesis after hypothesis may be enunciated only to be found wanting. As manhood is entered into, the individual learns that it is not essential to discover an immediate explanation for everything, and now begins patiently to accumulate data in the hope that wider experience and fuller com- mand of facts will eventually afford material for the right solution of a given problem. Thus at last, with the necessary experience, maturity and ripe powers of reasoning are attained. Pathology has passed through all these stages : through its infancy, in which medicine men and priests and augurs explained disease by fables ; through a long childhood of deference to Galenistic authority ; through a stormy youth of wild theorising and advocacy of system after system — iatro-chemical, iatro-mechanical, Brunonian, and many another ; through a period of reaction to the same, led by Virchow (extending roughly during the fifty years between 1845 and 1895), and now it may be said to have reached the age of maturity. There are those conscientious workers who continue to maintain that it is immature ; who hold that we have not passed the stage of working hypotheses as distinct from established theories ; who lay down that it is our duty still sedulously to accumulate facts without venturing to draw broad conclusions from the same. This, we think, is a mistaken opinion. There are, it is true, many territories which remain imperfectly explored ; Digitized by Microsoft® PEEFACE TO THIED EDITION ix but there are others which have been worked over so abundantly and have yielded so vast a harvest of facts, that unless we proceed to marshal these facts into order, and to classify them in due relationship one to the other, the danger is imminent that the accumulation becomes a very chaos ; that workers in one part of the territory, ignorant of the experience and material gained by those in another, will not merely waste their energy but work at cross purposes. In short, pathology will become a scientific Babel. The danger, indeed, is already with us ; we find sundry surgeons enunciating a pathology that is at variance with that of the physicians. Already in some countries, through a divorce between general patho- logy and bacteriology, there is a lack of eagerness on the part of the workers in the former to accept the data afforded by the latter ; and so huge has become our subject that no one man can have an equal familiarity with the recent advances in neuropathology, hsematology, teratology, and ante-natal pathology, immunity and the study of infection. This being so, it is urgent that some of those in- terested in medicine should give their time and energy not so much to the development of any one particular field, as to collecting and arranging the main data bearing upon the causes and development of morbid conditions, and the establishment of the deductions which may reasonably be gained therefrom. If with each passing year it is becoming less and less possible for any one individual to have a familiarity with every branch of pathology, the time has come to provide a common basis of fact and theory which is acceptable to and accepted Digitized by Microsoft® X INFLAMMATION by the workers in various branches, thereby ensuring an orderly development of the science of medicine in its many departments, a development which, starting from a common base, shall be harmonious. Such common basis is more particularly afforded by the data gained through researches into the process of inflammation. It cannot be too strongly emphasised that a knowledge of the inflammatory process is the foundation of all pathology. We see that ultimately all disease is due to the disturbance of the relationship and equilibrium between the organism and its surroundings ; from the point of view of the organism every such dis- turbance causes injury, provided that the local resources are not sufficient to counterbalance it forthwith. If we accept the definition laid down at the beginning of this article, viz. that (briefly) inflammation is the local reaction to injury, it follows that we must first gain a knowledge of what constitutes the inflammatory process if we are to understand disease of all orders. Even if certain diseases are not local conditions but general, affecting to a greater or less extent the whole organism, nevertheless such general conditions are but the summa- tion of a series of local disturbances, and must have originated from one or more local disturbance ; to master the general we must first understand the particular and the local. Thus, if our pathology is to be not a mere catalogue raisonn6 of names of morbid states, with precise de- scriptions of what those names indicate, but is to be a science — or, in other words, an endeavour to bring into order and relationship the phenomena of disease, and, Digitized by Microsoft® PEEFACE TO THIED EDITION xi recognising the relationship between phenomena, to deduce the laws which underlie and determine the individual cases of diseases — then, obviously, the study of the iniiammatory process is the natural starting-point for a right understanding of that science and what it can teach us. These considerations governed my treatment of the subject when, ten years ago, I was invited by Professor Allbutt to write the article on Inilammation for his new System of Medicine. I strove then to bring together all the data known to me bearing upon the subject of the reaction to local injury, and, cutting myself free from all the schools and established doctrines, I endeavoured conscientiously to select those facts which could not be gainsaid, and to draw from them the deductions which seemed most rational. There was here no attempt to bring forward anything that was new or that had not been already recognised by individual workers. At most it might be said that many of the facts brought forward, as also the method of approaching the subject, were new to the text-books. It has been a source of profound gratification that this article has from so many sources been accepted as authoritative, and that, when nine years later I came to revise it in the light of the abundant observations which had been published in the meantime, while there was much that might be added in amplifica- tion, there was little to correct. The teaching which in 1896 was to a certain extent novel is now in 1906 widely accepted. The revised article is here printed in book form in the hope that it may prove serviceable to the practitioner wishing to keep abreast of recent Digitized by Microsoft® xii . INFLAMMATION developments, and to the medical student who cannot be expected to purchase the large volumes of Professor AUbutt's System. And printing it thus I have to express my appreciation of the favour extended to me by Messrs. Macmillan and Co. in departing from custom and publishing as a separate entity what is portion of one of their larger works. In republishing it thus I have taken the opportunity to render it more complete and seasonable. The preseiit great interest shown in Sir A. E. Wright's brilliant researches upon opsonins demands that his observations obtain fuller description (though not fuller appreciation) than was accorded by me a year ago. Professor Bier's treatment of inflammation by induced hypersemia has likewise aroused widespread attention. The essentials of that treatment are here described, and I have been led to add what it is trusted will be a useful chapter on the application of the principles laid down in this work to the treatment of inflammatory states. It has seemed useful also to reintroduce in a modified form the para- graphs upon the haemal leucocytes which, present in the first, were omitted in the second edition of the article in Professor AUbutt's System, being there more properly treated in a new article upon the blood; and doing this, to call attention to the advances gained by Schridde through the employment of methods which permit the differentiation of the various forms of leucocytes within the tissues. MoNTEBAL, December 1906. Digitized by Microsoft® CONTENTS PART I A GENERAL SURVEY OF THE PROCESS OF INFLAMMATION CHAPTER I PAGE Provisional Definition 3 CHAPTEE II The Comparative Pathology of Inflammation 6 CHAPTER III The Experimental Production of Inflammation in NoN- Vascular Areas . 23 CHAPTER IV The Experimental Production of Inflammation in Vascular Areas 32 xiii Digitized by Microsoft® xiv INFLAMMATIOISr CHAPTER V PAGE The Experimental Production of Suppurative In- flammation . . . . 42 CHAPTEE VI The General Reactiox which mat AccoMPANr Inflam- mation . .51 CHAPTER VII Sdmmary of the Facts thus far brought forward 54 PART II THE FACTORS IN THE INFLAMMATORY PROCESS I. TEE PART PLAYED BY THE LEUGOGYTES CHAPTER VIII The Varieties and Classification of the Leucocytes 61 CHAPTER IX The same continued : Hematogenous and Histo-H^mato- genous Leucocytes . . .66 Digitized by Microsoft® CONTENTS XV CHAPTEE X PAGE HisTOGENOus Leucocytes . 72 CHAPTER XI Summary of Properties of Different Forms of Leucocytes . . 85 CHAPTER Xn Phagocytosis . 89 CHAPTER Xni The Humoral Hypothesis . 104 CHAPTER XIV The Cbllulo-Humoral Hypothesis . .107 CHAPTER XV Summary 121 11. THE INFLAMMATORY EXUDATION CHAPTER XVI The Fluid of the Exudate . .126 Digitized by Microsoft® xvi INFLAMMATION CHAPTER XVII PAGE The Solids of the Exudate: Fibrin Formation . .132 III. THE BLOOD-VESSELS CHAPTER XVIII The Part played by Blood- Vessels . 146 CHAPTER XIX On the Passage of Corpuscles out of the Vessels 155 IV. THE NERVOUS SYSTEM CHAPTER XX On the Part played by the Nervous System . 164 V THE CELLS OF THE TISSUES CHAPTER XXI Degenerative Changes 174 CHAPTER XXII Regenerative Changes 181 Digitized by Microsoft® CONTENTS xvii CHAPTER XXIII PAGE On Fibrous Hyperplasia and - its Eelationship to Inflammation . . ... 190 VI. TEMPERATURE CHANGES CHAPTER XXIV On the Increased Temperature op Inflamed Areas . 207 PART III GENERAL CONSIDERATIONS CHAPTER XXV On the Varieties of Inflammatory Manifestation . 213 CHAPTER XXVI On Systemic Changes consequent upon Inflammation 223 CHAPTER XXVII On the Principles of Treatment op the Inflammatory State . .... 227 Digitized by Microsoft® xviii INFLAMMATION CHAPTER XXVIII PAGE On" Adaptation : Conclusion . . . . . .232 EEFERENCES , . . . . 241 INDEX .... .251 Digitized by Microsoft® PART I A GENEEAL SURVEY OF THE PROCESS OE INFLAMMATION Digitized by Microsoft® Digitized by Microsoft® CHAPTEE I PROVISIONAL DEFINITION It is usual to begin the description of a morbid process by defining that process. In the case of inflammation, however, we have to deal with a process so complex, so modified by modifications of the many factors involved, and so variable in its manifestations according to the variety of its causes and the region of incidence, that the attempt to define it has proved a pitfall to pathologist after pathologist ; moreover, to advance a definition of the process at the beginning of this article in terms differing to any considerable extent from those employed by previous writers, would demand a criticism of the many previous attempts ; and in order that the definition put forward be duly supported, would necessitate an essay covering the whole field about to be traversed. Use of the Name. — Yet, in the meantime, inasmuch as divergent views are held of the limitations of the use of the name inflammation, a few words of introduction are advisable. Two courses are before us : either to employ the name strictly in accordance with the primitive definition, and thus only to include as cases of inflammation those states in which there are present redness, swelling, heat, and pain, rigidly excluding all cases in which these cardinal signs and symptoms are not present ; or, on the other hand, 3 Digitized by Microsoft® 4 INFLAMMATION pt. i departing from tradition, to include as inflammations all those morbid processes which seem to have a cause and progress inseparable from and merging into the cause and progress of the state characterised by the classical symptoms. The first course is impossible ; it is as though one were to declare that red phosphorus is not phosphorus because in externals generally it does not agree with the definition of the yellow form made years before the allotropic modification was discovered. We are now well agreed that of the classical signs, one, two, or three may be unrecognisable, and in fact absent ; and yet the condition of inflammation be undoubtedly present.^ The second is the only possible course, that, namely, which associates all those states which under suitable conditions may result in the production of the four classical states, and, moreover, originate from a common cause. Holding this view, it will in the meantime be well for me, in order to afford a starting-point for the description and discussion of the subject, to select from the many definitions one which is based not on symptomatology, but upon etiology, and indicates a common origin for all cases of inflammation. I would first note that which in this country has received the most cordial support, the definition given by the late Sir J. Burdon-Sanderson (1) in his well-known article in Holmes' System of Surgery : " The process of inflammation is the succession of changes which occurs in a living tissue when it is injured, provided ' A course allied to this has foimd favour of late years among some surgical pathologists, who, with Hiiter (2), would limit the use of the term to those cases and those only in which the classical signs, or the niajority thereof, are present and associated with suppuration, — they urge with Zahn (3) that inflammation only occurs when pyogenic micro- organisms are present, and state that when a wound heals aseptically it heals without inflammation. This modified course is equally impossible ; pyogenesis must not be confounded with inflammation. Digitized by Microsoft® OH. I PEOVISIONAL DEFINITION 5 that the iajury is not of such a degree as at once to destroy its structure and vitality." This definition includes too much. The hsemorrhage that occurs in the liver when it is injured, and the changes that there occur in the extravasated red corpuscles, are scarcely to be classed among inflammatory phenomena ; the atrophic changes which occur in the retina, when through injury it becomes detached, are due mainly to malposition and disuse rather than to the primary trauma. Grawitz (4) has put forward a definition based upon the same fundamental conception, but so worded as to exclude largely, if not wholly, the above objections ; for, as regards the second, it may justly be urged that atrophic changes are not reactive, but due to lack of reaction. Inflamma- tion, he holds, is the reaction of irritated and damaged tissues which still retain vitality. Either of these definitions has this great advantage, that, stating the cause, it clearly recognises inflammation as a process and not as a state. The manifestations of this process under favourable conditions — where the region injured is a loose and vascular tissue, and where the injury is sufficiently severe or extensive — are redness, swelling, heat, and pain : redness from the congestion of the vessels; swelling from the exudation of fluid and corpuscles from the congested vessels ; heat from the increased amount of blood in the region, and pain from the irritation of the terminations of the nerves in the region. To these four signs may be added a fifth, disturbance of fimction, brought about by this departure from the normal condition of the region. Under unfavourable conditions — where the region injured is dense or less vascular, or where the injury is less severe — one or all of these signs may seem wanting; nevertheless a minute examination of the tissues will show the same succession of changes as in the former case. Digitized by Microsoft® CHAPTEE II THE COMPARATIVE PATHOLOGY OF INFLAMMATION Accepting, then, this working definition, in order to arrive at a due comprehension of the succession of changes which we take to constitute the inflammatory process, it will be well with Metchnikoff^ (5) to institute a series of observations upon the reaction to injury exhibited throughout the animal kingdom from the lowest forms upwards to man. By this means we shall be enabled to determine what factors in the reactive process are from their constancy of primary importance ; what are common and essential, and what are superadded in the higher animals. The Response to Injury among the Protozoa. — Begin- ning our study with the lowest and simplest forms of life — forms so lowly that they have been regarded both as animals and as plants — we find even here phenomena accompanying the reaction to injury which throw light upon the inflammatoryprocess as seen in the higher animals. Taking as an example the amceba, we find, in the first ' The succeeding paragraphs are of necessity very largely an epitome of sundry portions of MetohnikofTs most pregnant work upon the comparative pathology of inflammation. By comparing them with the work in question, it will, however, be seen that they depart from it in several points ; more especially in dwelling upon the extracellular — excretory — activities of the wandering cells, and in bringing more prominently forward the response to injury on the part of the fixed cells. Digitized by Microsoft® OH. 11 COMPAEATIVE PATHOLOGY 7 place, that the nucleus plays an important part in this reaction. If, as Metchnikoff has shown, one of the larger amoebffi be cut in two, the region of injury becomes rapidly indistinguishable — the protoplasm of each moiety closes up, leaving no mark or scar : but of the two parts that which retains the nucleus grows and proliferates ; the other disintegrates in a longer or shorter time. As I have shown elsewhere (6), from every consideration we are forced to regard the nucleus as the dominant constituent of the cell, controlling its higher activities ; the nucleus is essential for continued growth and for reproduction. Or injury may induce changes in the protoplasm of the entire amoeba : thus Miss Greenwood (7) points out that, without necessarily bringing about death, the interrupted current or an aqueous solution of thymol leads to a process of exudation or extrusion of clear hyaline spheres, ot of spheres holding crystals and granules, from the surface of the organism — a process resembling that occasionally seen in the cells of an inflammatory area in higher animals. Nor is this all ; apart from changes in the structure of these unicellular animals, differences may be seen in the behaviour of amoebae towards foreign bodies. According to Le Dantec (8), amcebte ingest non-irritating foreign substances indifferently, provided they be sufficiently small. It is, however, doubtful whether absolute inert particles are ingested. More recent studies suggest that there must be adherent to, or contained in the particles some- thing that affects the surface of the amoeba, or otherwise that a change in the physical condition of the surface layer of the cell precedes the formation of a pseudo- podium. Around each particle so ingested a vacuole is formed, and the fluid in this becomes increasingly acid, and at the same time digestive. Krukenberg (9), Eeinke (10), and Miss Greenwood have conclusively proved Digitized by Microsoft® 8 INFLAMMATION pt. i these and similar food vacuoles in the amoeba and other Protozoa to contain a pepsin or digestive ferment, which, as Le Dantec has shown by very delicate tests, exerts its action in an acid medium (the general protoplasm of the cell-body being alkaline) ; this digestive process leads to the solution of food-stuffs, preparing them to be taken up by the protoplasm of the organism. Such portions of the foreign substances as are incapable of digestion become sooner or later extruded, It; is by this formation of digestive vacuoles that the amoeba acts upon and destroys bacteria, diatoms, and other microbes ingested by it. There are, however, microbic forms around which it would seem that no proper vacuolation is developed, or if developed, the acid digestive fluid is neutralised by substances dis- charged from the parasites ; where this is the case, instead of destruction there is continuance of vitality and actual multiplication of the invading or parasitic form, leading to the eventual death of the amcEba. Metchnikoff has observed this chain of events in one of the amoebae which ingests and becomes the host of a minute rounded form, the Microsphsera. Phenomena of like nature may be observed among the ciliate and flagellate infusoria. Here it is worthy of note that bacteria, which, as we shall see, are the main causes of inflammation in higher animals, are in these lowly forms an important, if not essential, source of nutrition. So far it has not been found possible to gain pure cultures of the amoebae : in other words they are unable to obtain adequate nourishment from the various media of the laboratory. It has been found, however, by Frosch, Mouton, and others (11), that if certain of the commoner forms be isolated, placed in a suspension of a pure culture of the bacillus coli, or certain other species of bacteria, and then be " sown " upon the surface of a tube of sterilised agar of broth, active growth and miiltiplication ensue, the bacilli being taken up and Digitized by Microsoft® CH. II COMPAEATIVE PATHOLOGY 9 used as food. While these phenomena may primarily be regarded as the method employed by the Protozoa for the assimilation of food-stuffs, they also are clearly the means whereby the Protozoa defend themselves against living organisms which have gained entrance into them, and thus form the reaction to possible injury ; for when in certain cases the means of defence are overcome, the parasitic organisms gain the upper hand and lead to death. Chemiotaxis. — ^There is yet another reaction to injurious influences exhibited by the Protozoa into which it is necessary to enter at some length. This is exhibited by the amoeba, but can be and has been most fully investigated in the myxomycetes — multicellular forms which can with equal propriety be classed as animals or plants, although usually they are included among the latter. These organisms form large plasmodia (masses of protoplasm, that is), in which, under ordinary conditions, the nuclei are the only indication of the individual cells which by their fusion have formed the masses. They are to be met with in leaf mould, and on the surface of moist decaying wood, over which they creep with an amoeboid movement ; and inasmuch as they may attain great size — some species attaining twelve inches or more in length — they form admirable material for biological study. Twenty-five years ago Stahl (12), investigating one of these myxomycetes (the JEthalium septicum, an organism found in tan-pits), showed that if placed upon a moistened surface close to a drop of infusion of oak -bark, the Plasmodium moved actively towards and into the infusion ; if placed similarly near to a solution of glucose (0'5 per cent) it moved with equal rapidity away, and so also in the case of solutions of various salts. These observations of Stahl were (if we except Engelmann's Digitized by Microsoft® 10 INFLAMMATION pt. i observations in 1881 upon the tendency of sundry bacteria to remove from regions poor in oxygen to those where oxygen is present in abundance) the iirst of a series of observations upon the attraction and repulsion of plants and portions of plants by chemical substances. To this property Pfeffer (13), who has made the fullest series of studies upon it, has given the name of chemiotaxis, in place of Stahl's narrower " trophotropism " ; and one speaks of a positive or a negative chemiotaxis according to the attraction or repulsion exerted. If, as Metchnikoff has pointed out, the advancing edge of one of these Plasmodia (of Physarum) be injured by cauterisation, the region of injury dies ; the protoplasmic currents, which , had been advancing, reverse themselves abruptly, and within an hour the plasmodium has moved away, leaving Ithe debris of the destroyed region behind. These experi- ments are so simple, and the results obtained seem so natural, that it may be asked whether it be worth while to attach a name to this property of living matter. Yet the name is in itself an aid to bearing these properties in mind ; and, as will be pointed out later, the recognition of them is of material help in solving certain of the difficulties that present themselves in the study of inflammation in the higher animals. It may be well to note here sundry investigations which throw light upon the essential nature of chemio- taxis and, indeed, upon the motility of living matter.^ In the first place it has to be recognised that this property of moving towards or from other substances is not a specific attribute of living protoplasm ; it exists as between substances that are not living : in fact, using inert matter, chemiotactic phenomena and even the 1 A fuller account of many of the data bearing upon the physical basis of chemiotaxia is to be found in Wells' Chemical Pathology, Philadelphia, W. B. Saunders Co., 1907,page 208. Digitized by Microsoft® CH. II COMPAEATIVE PATHOLOGY 11 throwing out of pseudopodia and the engulfing of particles can be reproduced with striking fidelity. If, as Bernstein (14) has shown, a drop of mercury be placed in a dilute nitric acid solution and now a crystal of potassium bichromate be let fall in its neighbourhood, so soon as with solution of the salt the yellow area of diffusion impinges upon the quicksilver, this exhibits active movement towards the crystal and flows around it as though to ingest it. If the crystal be moved away, the mercury follows. Or again, as Ehumbler (15) has demonstrated, a drop of clove oil let fall into a freshly made mixture of glycerin and alcohol exhibits active amoeboid movement. It may be recalled that alcohol and glycerin do not easily mix, and that thus there are in the mixture regions in which now the alcohol and now the glycerin is the more concentrated. The clove oil can mix with the alcohol but not with the glycerin. If close to the clove oil there be dropped a little strong alcohol, the oil globule moves actively towards it with pseudo- podial motion. Again, a drop of chloroform in water acts in a most life-like manner, flowing up to some substances presented to it and flowing away from others. Let, for example, a fine thread of shellac be made to touch it, and the edge of the chloroform droplet extends along it, just as the cytoplasm of a leucocyte flows along a chain of anthrax bacilli, and with this the shellac softens and becomes coiled up within the drop until in this way a thread of shellac six times the length of the diameter of the drop becomes included within it. The explanation of these phenomena is, briefly :- — modification of surface tension. Physicists recognise a force — cohesion force — acting between the particles of a fluid and attracting the one to the other. This force differs in intensity for different fluids. Thus in the centre of a drop of one fluid suspended within another Digitized by Microsoft® 12 INFLAMMATION pt. i the forces acting upon the particles are equal in all directions. At the surface the cohesion force acting on the inner aspect of the particles may be widely different from that acting upon them from the fluid of suspension without ; they are, in fact, subject to unequal pressure. It is this force and this . difference in force that constitute the surface tension, and that further leads the suspended fluid to assume the shape of a sphere. Now let the cohesion force of the outer fluid be modi- fied locally, so that it approximates to that of the suspended drop : it follows that in the region of this modification the surface tension of the drop will become less than that on the opposite side of the drop. The result must be what happens when a thin-walled distended rubber ball is weakened on one side : namely, the droplet gives towards that side, and its contents stream towards the region of concentration of the intro- duced salt or fluid. When the cohesion force of the suspending fluid is locally reduced, then on the contrary the droplet flows away. Thus it would seem that pseudopodial activity is at basis dependent upon the surface tension of the ectosarc of the amoeba or leucocyte. As to what in living matter pre-eminently induces alterations in surface tension, the researches of Hardy, Loeb, and Brailsford Eobertson would seem to afford a clue. The extreme sensibility of protoplasm to changes in its environment appears to depend upon the amphoteric nature of the constituent molecules of living matter, i.e. upon their capacity to combine with both acids and bases, to form what Loeb (16) has termed ion proteins. As Hardy (17) expresses it, "their electrical characters are conferred upon them by the nature of the reaction, acid or alkaline, of the fluid. If the latter is alkaline the Digitized by Microsoft® CH. 11 COMPAEATIVE PATHOLOGY 13 particles become electro-negative and vice versa." As Brailsford Eobertson points out (18), when the diffusion of ions in the surrounding medium is uneven, as these act upon the protoplasm causing in that a dissociation of the ions attached to the protein molecules, the different rates at which positive and negative ions travel will bring about that at one side of the cell there will be a greater or less accumulation of one or other type of ion, with, as a result, increased or diminished surface tension. In this curiously unstable equilibrium of the constituent molecules of living matter, and in the ease with which they dissociate and enter into combination with surrounding ions, would seem, therefore, to lie the explanation of alteration of surface tension, motility and chemiotaxis. In the myxomycetes another point can be made out. Stahl observed that the plasmodium of Fuligo, which at first moves away from a two per cent solution of common salt, will after a time (more especially if it has suffered from lack of water) adapt itself to the solution, advancing its pseudopodia or protoplasmic processes into it. With other myxomycetes the same adaptation has been observed. That is to say, by use or adaptation a negative may be transformed into a positive chemiotaxis. To this change I shall have occasion to revert. A similar, and suggestive, series of adaptations has been noted by Musgrave and Clegg (19) in their studies upon amoebse. They note that these in their natural environment — the pathogenic forms in the large intestine, for example — are selective, feeding upon only one of the many surrounding species of bai3teria. Away from that natural environment they grow abundantly upon the surface of agar tubes in association with this one form. By the gradual addition of pure cultures of another bacillus, with which, at first, growth is not possible (the amoebse not taking them up, and starving as Digitized by Microsoft® 14 INFLAMMATION pt. i a consequence), the amcebse first become accustomed to this foreign form, then take- up occasional individuals, until eventually they will feed upon and grow in a pure culture of the second form, in the total absence of members of the first species. Nay, more, these observers noted that one particular amceba, isolated from Manila tap -water, and grown in conjunction with a species of bacteria present iu that water, set up abscess-formation when inoculated with it into the liver of animals of the laboratory : from such an abscess growths of the amoeba could be obtained in association with the microbes in question. But if passage were made through two more animals of the same species, setting up in them liver abscesses, it was found impossible to gain growths in like manner. The amcebee were there, but growth in the tissues had changed their habits. They had clearly accustomed themselves to a wholly different form of food — presumably to cell-products of the organism ; a point which throws light upon the frequent occurrence of tropical abscesses of the liver, in which amoebae are present without associated bacteria. The Response to Injury among the Metazoa. — Passing from the Protozoa to the Metazoa, we reach immediately (or almost immediately) a series of beings in which the division of labour among the cells has led to the development of three cell-layers — an outer ectoderm, an inner endoderm, and an intermediate layer of mesoderm. Even in the Very lowest forms among the Metazoa it is noticeable that of these three layers there is one, the mesoderm, whose cells have the especial function of reacting when any irritant or injurious agent gains entrance into the organism. Taking what are perhaps the simplest forms in which to observe the relationship and properties of these layers, Metchnikoff has studied these results of injury in the larval forms of Astropecten and Digitized by Microsoft® OH. 11 COMPAEATIVE PATHOLOGY 15 other echinoderms. At one well-recognisable stage these larvce resemble little more than the gastrula stage of the embryologist ; the endoderm or hypoblast appears as a cul-de-sac — an invagination of the ectoderm or epiblast — while the mesoderm is represented by amoeboid cells, budded off from the endoderm, lying or floating in the Fig. 1. — 1. Larva of AstropecUn, modified from Metclmikoff to show eTW?, endoderm ; ect, ectoderm ; mes, mesodermal wandering cells ; jil, Plasmodium of mesodermal wandering cells formed around, foreign tody which has punctured the endoderm. 2. The Plas^nodium, from the same larva, highly magnified ; nucl, nuclei of the fused wandering cells ; /, spicule-s of foreign matter around which the cells have collected. semiliquid substance filling the general body-cavity.'^ The ectoderm is so delicate that any sharp substance can ' As indicating the earliest stage of these wandering cells it is note- worthy, as MacBride (20) has pointed ont, that in the gastrula of Echinus esciilentus two forms of wandering mesenchyme cells are present in the body-cavity : one obviously stellate, and attached to other similar cells and to the body -wall by long processes; the other, rounded forms (amoebocytes), which, while appearing free, are connected with neighbour- ing cells and the body-wall by means of excessively fine threads, along which they appear to travel. The cells at first are therefore only relatively free. Digitized by Microsoft® 16 INFLAMMATION pt. i readily penetrate into the body-cavity ; and, when this happens, it is noticeable that the wandering mesodermal cells make their way to the foreign body, attach them- selves to it, and fuse into plasmodial masses, thus forming a wall, as it were, around the invading substance, and cutting it off from the general body system. Here, then, in an organism possessing neither nervous nor vascular system, the reaction to injury, when that injury has not been sufficiently intense to cause destruction of the outer layer of cells, is simply and solely confined to the wander- ing cells of the body ; there is no effusion of fluid ; there is not necessarily phagocytosis on the part of these cells ; any digestive and destructive action on their part — any attempt in this way to remove the foreign body — must then be by excretion, hy extracellular action. At the , same time, this fusion of the cells and formation of a Plasmodium around foreign substances of greater diameter than the individual mesodermal cells may be looked upon as a mechanism whereby the equivalent of intracellular digestion is gained. But, as among these low forms cases occur in which, without the formation of plasmodia, the cells perform their destructive action upon bodies of larger size than themselves, we do not lack examples of what must be considered as excretory destructive powers on their part. That these cells in the echinoderms are also capable of destroying minute foreign bodies by intracellular action, that is, by phagocytosis, has been demonstrated in the larger transparent larval form known as Bipinnaria asterigera; on introducing bacteria under its ectoderm the mesodermal cells are seen to approach, and by their long pseudopodia to adhere to and ingest the still living motile bacteria, which are rapidly digested. Besides this reaction to injury on the, part of the mesodermal cells, a further response is exhibited to a remarkable degree among the lower Metazoa — I refer to Digitized by Microsoft® CH. n COMPAEATIVE PATHOLOGY 17 the great power of regeneration of lost parts, of cell- proliferation, leading to the reproduction of destroyed regions. This power is best seen in the classical example of the Hydra, which may be cut into many pieces, each (save the tentacles) capable of growing, so that in a relatively short time it becomes a fully formed individual. It is interesting to note in relation to the frequent tendency towards hyperplasia and excessive growth following upon injury in the higher animals, that among low forms, such as Hydra and Cerianthus, the same tendency is yet more strongly marked. Thus, as J. Loeb (21) points out, if an incision be made in the stem of a Hydra, a whole new oral pole, provided with tentacles, will branch out from the region of cell-destruc- tion. In the actinian Cerianthus the process is not quite so extensive ; yet from the lower lip of a lateral incision a set of tentacles develops in all respects similar to those around the moutli. Ascending to the Worms, we find that the protective agency devolves upon mesodermal cells suspended in the perivisceral fluid, and again forming the peritoneal endo- thelium. We arrive, that is to say, at a stage in which a lymphatic system may be said to be present : for the spaces in which the free corpuscles lie are strictly homologous to the lymph - containing spaces of the vertebrate organism, and these corpuscles may be regarded as lymph - corpuscles ; the peritoneal endo- thelium corresponds with the mesodermal peritoneal endothelium of vertebrata. It is the fixed as well as the wandering cells that take part in the process. Among the Annelids the process of reaction to injury may be well followed in the earthworm by studying the sequence of changes that occurs around the gregarines which infest the male genital organs. While these parasites are active they by their movements prevent c Digitized by Microsoft® 18 INFLAMMATION pt. i the adhesion of the wandering cells ; but so soon as they pass into the resting stage antecedent to spore-formation, the cells form a thick mass around them. The parasite on its part forms a thick cyst-wall ; nevertheless it may not infrequently be observed that, despite this protection, the parasite changes its appearance under the action of the surrounding plasmodium, and in fact is killed. While this is happening no change could be detected by Metchnikoff in the neighbouring blood-vessels ; these appear to remain completely inactive : , no exudation is noticeable nor any recognisable change in volume. The nature of the injury inflicted without doubt influences the character of the reactive process. Thus causing direct injury, either by passing a thread through the body, or by cautery, Messing (22) found that in the earthworm and leech regenerative changes are both more pronounced and of more rapid development than is the accumulation of wandering cells. In six hours the injured epithelium might show definite signs of regenera- tion, while at this period but few mesodermal cells had collected. While among the Worms a well-developed and closed vascular system is not infrequently present, in other animal forms, which in most respects present a much more complex and advanced development, namely, in the Molluscs, Arthropods, and Tunicates, this is not the case. In these the blood pours from the tubular heart sooner or later into the lacunte of the general body.-cavity ; and whether veins and capillaries (i.e. finer vessels lined with endothelium) be absent (as is most usual), or present (as in the Cephalopods), the blood is sucked back from the body-cavity into the heart. This incomplete circulation, interesting as it is in connexion with the development of the vertebrate circulation, is interesting also because its incompleteness in these large and widespread classes of Digitized by Microsoft® CH. n COMPAEATIVE PATHOLOGY 19 animals prevents reaction to injury from being associated with vascular changes. The blood in these animals, circulating through the ramifications of the body-cavity, is evidently a mesodermal fluid, if it may be so termed. Its corpuscles are clearly mesodermal ; and without going into full details as to the properties of these corpuscles, it may be said that they represent an interesting series of stages in the subdivision of labour. For example, as Hardy (23) has shown us, in a low form of crustacean like BapJinia (ihe water-flea) but one form of cell is present, whereas in the highly developed Astacus (the crayfish) there are three distinct fornas of leucocytes (no red corpuscles being present), each of which appears to have distinct functions. The one form in Daphnia has the property of taking up fat globules and food particles from the alimentary tract, foreign particles such as granules of carmine or Indian ink, and the spores of parasites {Monospora, Metchnikoff) ; it is granulated, containing minute spherules which stain with basic aniline dyes (basophil granules), and in certain circumstances it may be seen to explode with lightning-like rapidity. In the higher Astacus there are in the circulating haemal fluid two varieties of cells : one is extraordinarily explosive ; when removed from the body-cavity it gives off fine blebs or vesicles of its substance with such rapidity that, unless the greatest care be taken, nothing is seen of the cell save its nucleus ; this form is phagocytic : the other form is far more stable, and is loaded with large spherules which have a great affinity for acid dyes — they are eosinophilous — may be actively extruded, and undergo decomposition ; these cells never act as phagocytes. A third form, with basophil granules, is rarely found in the blood, and then only as the result of special stimuli ; but it is present in considerable numbers in the peculiar tissue which forms Digitized by Microsoft® 20 INFLAMMATION pt. i a sheath around certain of the arteries — Haeckel's " Zellgewebe " ; this form is phagocytic, and can be seen to contain globules of ingested fat. Metchnikoff (24) demonstrated, in his most remark- able study iipon a disease of Daphnia caused by the entry of the spores of a yeast-like organism (the Monospora) into its body -cavity, that its one form of leucocyte can be seen to react swiftly towards the spores ; the cells approach them, form a plasmodium around, and eventually digest and destroy them. If, on the other hand, in consequence of their great numbers or the relative paucity of the leucocytes, certain of the spores be not attacked and develop uninterruptedly into mature torulae, the leucocytes show no tendency to approach them — in fact, their neighbourhood leads to the explosion of the leucocytes — and the torulse, multiplying, lead to the death of the organism. Often, again, brown eschars may be recognised upon the transparent carapace of a Daphnia, due to injuries by other individuals ; beneath these scars are to be found masses of leucocytes which remain in the region of injury until the cells of the tissue have proliferated and there is complete union and repair. In addition, then, to the immediate reparative and protective reaction of the leucocytes, there is exhibited among the higher invertebrata a later reaction in the shape of proliferation of the fixed cells ; nay, at times the proliferative and regenerative process may be the more pronounced. This proliferation can be very gTeat ; and cells of all forms, whether of hypo-, meso-, or epiblastic origin, and tissues so highly developed as the muscular and nervous, may participate in it. In illustra- tion of the ample power of tissue -reproduction after injury possessed by these animals, I need but mention the trite examples of the reproduction of the hinder Digitized by Microsoft® COMPAEATIVE PATHOLOGY 21 Pig. 2. — A, A paphnm (water-flea) invaded by the parasitic yeast, Monospom. The deep shading, more particularly below the intestinal canal (a), is due to the mass of spores which have penetrated into the body-cavity. B, Anal end of an infected Daphnia. The elongated spores are to be seen in the lumen of the gut (&), in the walls of the same, and others which have penetrated the walls and have entered the body-cavity are seen with leucocytes attached (c, c). C, Stages in the development of Monospora : 1, Individual elongate oval torula; 2, a torula budding ; 3, do., later stage ; 4, much elongated torula prior to spore-formation ; 5, torula with contained spore. D, Stages in the destruction of the spores : 6, spore with two leucocytes attached ; 7, 8, later stages of erosion and digestion. — Metohnikoff. Digitized by Microsoft® 22 INFLAMMATION pt. i segments of divided worms, and in crustaceans the restoration of injured and cast-off claws and appendages. Many more instances might be given to show that the reaction to injury remains essentially a reaction on the part of the wandering and fixed mesoblastic cells of the organism, followed in sundry cases by proliferation of the fixed epi-, meso-, and hypoblastic cells, and by repair where these have been destroyed. Although these arthropods, molluscs, and tunicates have a vascular system, yet, since this is open, changes in it, did they occur, could scarcely modify the inflammatory process. The Response to Injury among the Vertebrata. — If now we pass to the vertebrates, the picture presented is far more complex ; not only do these present a highly developed nervous system, but the blood is enclosed in a complete vascular system. It is but just to call attention again to the fact that many authorities deny that up to this point we are justified in speaking of inflammation, urging that inflammation can only be said to be present when there is " flaming," i.e. increased redness and heat, due to increased blood-supply, that is to say, to vascular changes. While this position is etymologically correct we cannot accept it, because, as will be pointed out in the next chapter but one, we find that where this " flaming " is present, the process, never- theless, in essence, is identical with that in the lower animals devoid of a complete vascular system. Digitized by Microsoft® CHAPJER III THE EXPERIMENTAL PRODUCTION OF INFLAMMATION IN NON-VASCULAR AREAS Let us begin with the succession of changes that occurs in the simplest case, namely, in a non-vascular area, in one of the lowest vertebrate forms — for instance, in the embryonic Axolotl ten to fifteen days old ; let us curarise it, and apply a minute crystal of silver nitrate to the side of its flattened transparent tail-fin, washing away the remains of the crystal with salt solution ; or again, we may pass into the tail a small needle filled with finely powdered carmine. By either procedure a certain number of cells is destroyed. The neighbourhood of the injury now becomes swollen, and the surrounding cells tumefied, vacuolated, and less refractile. This is the first stage — that of injury and modification of the surrounding tissue. In a little time a few wandering cells (leucocytes) approach the injured region ; by the next day these are present in fair numbers, and can be seen to have taken up the particles of carmine or debris of the destroyed tissue. This is the second stage — that of immigration of leucocytes. There are no vessels in the transparent fin of these young axolotls, no dilatation of those nearest to the fin, and no diapedesis. All the leucocytes that pass to the part are pre-existing wander- ing cells of the connective tissue, — a point of some little 23 Digitized by Microsoft® 24 INFLAMMATION ft. i importance in connexion with the origin of certain of the pus-cells in the suppurative process of higher animals. The third stage is that of repair, of proliferation of the injured epithelium, return of the fixed cells of the tissue to their previous state, and emigration of the wandering cells. A very similar progress of events occurs if the ex- periment be repeated upon the tail-fin of the young Newt. The same rapid alteration in the large branched connective-tissue cells (which become vacuolated as their long processes are drawn in and shortened), and the same immigration of motile cells from the surrounding connective tissue are to be seen ; but here we now find the earliest evidence of vascular participation, for, accord- ing to Metchnikoff, complete arrest of the circulation may occur in the nearest vascular loop. By the next day the parts have returned to the normal condition. If from these cases we pass to mild inflammatory disturbances affecting the non-vascular regions of animals far higher in the scale, we again discover a like process of events. For this purpose the cornea affords the tissue of election ; in health it is absolutely non- vascular, perfectly transparent, and so thin that it can readily be examined microscopically. The cornea of mammalia, and indeed of vertebrates in general, is formed of fibres which run in layers parallel to the surface. These fibres, while roughly arranged side by side and parallel to one another in any given layer, are placed at an angle to the fibres of the layers above and below. Although free from blood-vessels the cornea is far from being devoid of channels along which lymph freely passes. Between the several layers there exist spaces in which lie the flattened connective-tissue cells of the organ ; and, by means of numerous fine channels, these spaces around the cells are connected with similar Digitized by Microsoft® CH. in IN NON-VASCULAK AREAS 25 spaces lying in front, behind, and at the sides. Through this rich anastomosis of channels there is a free flow of lymph. These channels are really continuations of the body-cavity of the animal; they represent, and in fact play the same part as the single body-cavity of such a simple form as the larva of Astropecten, while the cells lying in the spaces are mesoblastic cells which have become fixed. Few studies are better calculated to impress the investigator with a sense of the depth of the well at the bottom of which truth lies, than a research into the abundant literature dealing with observations upon the stages of the inflammatory process as it occurs in the cornea, and with the deductions therefrom. The adherents to successive forms of inflammatory belief have found in experiments upon this simple tissue ample support for their particular creeds. Selecting from the many observations those which have stood the test of time, I will begin with the simplest, and pass on to those dealing with an increasing intensity of the inflammatory process. (i.) If, as Senftleben (25) first pointed out, the centre of the cornea of a rabbit be washed with a strong solution of zinc chloride, then, in favourable cases, although the epithelial covering be gravely injured, there may be no actual rupture of the outer layers of the tissue. Such a cornea removed twenty-four hours later may show no sign of migration of leucocytes — no sign, again, of congestion of the vessels at the periphery. The only indications of injury and reaction may be the destruction of the corneal corpuscles immediately beneath the cauterised area, and the appearance of a zone sur- rounding this in which the, corneal corpuscles appear enlarged, distinct, and tumefied. The process may continue and advance insensibly to repair without the Digitized by Microsoft® 26 INFLAMMATION pt. i intervention of leucocytes ; the hypertrophying cells of the " granular " zone eventually undergoing karyokinesis, and thus by multiplication replacing the corpuscles destroyed. Here, then, necrosis and new growth of the fixed cells of the tissue are the only recognisable factors in the process of repair of injury. It must be confessed that the conditions permitting this simplest form of reaction are of rare occurrence ; it is worthy of attention that they can exist. (ii.) By a slight modification of the preceding condi- tions another factor may be brought into play. If, after cauterisation in the manner above described, a break be made into the cauterised surface ; or if, again, without cauterisation, a little of the corneal tissue be removed, then in a few hours a small whitish opacity is to be noticed within the corneal tissue in the immediate neighbourhood of the break in the continuity, and upon examination this opacity is found to be due to a massing of small round cells. As there is at this moment no sign of proliferation of the connective-tissue cells of the cornea, these newly collected cells can only be leucocytes ; and further examination of their properties proves them to be such: there is, however, no evidence of dilatation of the peripheral vessels, no indication of diapedesis through their walls. The leucocytes, therefore, can only have entered into the wound from the cornea itself and from the conjunctiva and the lacrimal fluid bathing it.^ In this experiment the inflammatory process is repre- sented by destruction of tissue and immigration of leucocytes, followed by repair ; neither the vascular nor the nervous system play any part in it. We are forced to the conclusion that the leucocytes have massed them- 1 It is to be noted that the lacrimal fluid contains even in perfect health, occasional leucocytes which have found their way into it through the tissues. Digitized by Microsoft® CH. Ill IN NON-VASCULAE AEEAS 27 selves in the injured area purely on their own initiative; and that there must be an attraction, a chemiotaxis or chemiotropism, leading them actively to approach the region of cell-destruction. (iii.) Or we may proceed a step farther. A fairly severe aseptic injury can be produced by cauterising the centre of the cornea. In thus treating the pigeon's cornea Goecke (26) noted that the wandering of cells towards the damaged area is first visible twelve hours after the injury, and then proceeds from the periphery. Obviously the wandering cells are white blood-corpuscles, and pass from the peripheral vessels. In twenty-four hours the process and the accumulation of round cells reach their climax. Some of the new-comers break up, others, according to Goecke, show signs of division. But soon these foreign cells commence to wander away, and at the end of thirty-six hours scarce any are left. Turning to the fixed cells of the part, it is deserving of note that, before ever a leucocyte has reached the injured area, the corneal corpuscles, bordering upon the area of cauterisation, show evident signs of enlargement and growth. On the second day there are indications of active proliferation ; and these newly formed corneal corpuscles behave exactly like certain white blood- corpuscles, from which they are indistinguishable. The vexed question of the relative part played by the wander- ing white corpuscles of the blood and wandering young connective-tissue cells will be touched upon later. It is, however, well to impress upon the reader that, at a certain stage, what we may term histogenous and hsemato- genous wandering cells are wholly indistinguishable by our present methods of study. The fight has been par- ticularly bitter regarding these cells in connexion with this very subject of experimental keratitis. (iv.) The observations made upon these three more Digitized by Microsoft® 28 INFLAMMATION pt. i simple cases help us materially to understand the series of events which occur in more intense inflammation of the cornea, such as that produced by injuring the surface and causing the entrance into the injured region of a small quantity of a pure culture of the pyococcus aureus. This may be accomplished by injecting the culture into the centre of the healthy cornea by means of the needle of a Pravaz syringe (Jacobs) (27). The micrococci so introduced grow rapidly, the growth so extending along the lymph-spaces that a branched mass of the microbes is produced, having the spot of inoculation as centre. Around the growth as it extends may be seen a sharply marked area in which the corneal corpuscles show evidences of degeneration ; the nuclei stain faintly, and the corpuscles, speaking generally, have a shrunken appearance. Here, again, the first effect of a microbic, as of a simple chemical injury, is to bring about degenera- tion of the fixed cells of the tissue. Within eighteen hours the zone of proliferating cocci and cell-degeneration is well marked ; and now the second stage begins to be clearly manifest, namely, the determination of leucocytes to the seat of injury. Within twenty-four hours there is a dense packing of these corpuscles around the central degenerated area, and great numbers of leucocytes may be seen converging along the lymph -spaces from the periphery of the cornea. This is the second stage of the process, the first stage of obvious reaction to the injury inflicted by the invading micro-organisms. If, as by Cohnheim^ (28) in his original experiments upon the injury to the cornea, more careful examination be made into the stages of the determination of leucocytes, it can be seen that this determination is closely related to 1 There can be no question that Cohiiheim in his experiments induced not a simple keratitis but one which in the absence of aseptic precautions rapidly became infective and suppurative. Digitized by Microsoft® CH. Ill IN NON- VASCULAR AEEAS 29 changes set up in the veins at the periphery of the cornea ; they become more prominent, the region has a congested appearance, the smaller as well as the larger vessels are dilated, and there is abundant evidence that the leucocytes are passing out from the contained blood into the surrounding lymph-spaces. Indeed the accumu- lation of leucocytes shows itself first at the periphery of the cornea near the vessels, and gradually approaches the region of injury. Into the mechanism of this diapedesis, and into a fuller description of the changes that take place in the blood-current in these distended vessels, I shall enter later when discussing the changes in highly vascular regions. Suffice it to say here that no distinc- tion can be made out between the behaviour of the leuco- cytes in the previous experiment, when they entered the wounded area from the external surface, and in this where the majority find their entrance from the blood ; as in the previous case the part played was evidently active, so must it be here also. "We cannot arrive at any other conclusion than that some attractive force leads to their determination towards the inflammatory focus. It is the polymorphonuclear leucocytes which at first most actively migrate. As Councilman (29) points out, in experimental pyococcic inflammation, as early as fifteen minutes after inoculation of the centre of the cornea a greater number than usual is seen in the conjunctiva. A more granular, more sluggishly amoeboid form follows, most numerous in eighteen to twenty-four hours, while lymphocytes are not visible until the fourth day, and then do not so much pass out of the vessels as from the sheath of lymphoid tissue surrounding them. We can easily show, by repeating the experiment, that many of these leucocytes take up and contain numerous cocci, while other cocci remain free in the tissue-spaces. Many of the leucocytes degenerate and present a broken-down Digitized by Microsoft® 30 INFLAMMATION appearance ; and, as at the same time an increasing area of the corneal tissue becomes disintegrated, an ulcer appears. According to the virulence of the culture and the reaction on the part of the organism, the process may now extend, a larger and larger portion of the corneal tissue becoming affected ; or, on the other hand, there may Fra, 3. — Mild grade of keratitis ; commencing regeneration after forty-eiglit liours. 1. Peripheral zone of corneal corpuscles, showing enlargement with nuclear multi- plication. 2. Zoneof degenerating granular corneal cells (?j). 3. More central area of cells (c) destroyed and broken up by the action of the caustic, a. Processes from proliferating corneal cells, with nuclei, the products of direct nuclear division, advancing into region of irritation and degeneration. — After Senftleuen. be an arrest of the progress, the massing of the leucocytes preventing, as a barrier, the further extension of the micrococci into the lymph-spaces ; ^ while at the same time there is an advance of newly formed capillary vessels into the previously non- vascular tissue. It is to be noticed that the blood-vessels at the periphery of the cornea are ^ Into the details of this action I shall enter more fully later. Digitized by Microsoft® CH. in IN NON-VASCULAE AEEAS 31 prominent and dilated, and from them fine new vessels with very delicate walls pass towards the injured region. At the same time many of the corneal corpuscles, outside the area of destruction, can by appropriate staining be seen undergoing mitosis and proliferating. Thus the active repair of the tissue is initiated. The regenerative process is best observed in young animals by the use of caustics without causing a break in the continuity of the surface. Twelve hours after injury indications of cell- growth may be made out ; in twenty-four hours mitoses are numerous, but occur only in the zone immediately surrounding the necrosed area. The corneal corpuscles become larger, their protoplasm more abundant ; the cell-bodies stain more deeply ; the nuclei become more rounded and also more deeply stained ; the cells give off long processes — always towards, never away from, the necrosed area — and with division of the nuclei the young nuclei make their way into the processes, and so into the dead tissue. In this way new typical corpuscles are formed in the course of the branches, which further show abundant cell -inclusions ; in other words, the growing tissue-cells feed upon the migrated leucocytes. Digitized by Microsoft® CHAPTEE IV THE EXPERIMENTAL PROBUCTION Oi' INFLAMMATION IN VASCULAE AREAS From this study of inflammation, as it occurs in a region primarily devoid of blood-vessels, let us now pass on to the more complicated process of inflammation in vascular areas ; and, as in the previous case we considered an ascending or advancing series of reactive changes, so here let us begin with the slightest injury associated with the mildest reaction, and pass onward to states in which the inflammatory manifestations are more and more pronounced. (i.) If an incision be made with a perfectly aseptic instrument into the skin, also rendered aseptic, and be so made as to divide the dermis and tissues immediately below, without at the same time injuring any large vessel, it is the common experience of modern surgeons that repair takes place with the minimal amount of change recognisable as inflammatory. Eepair takes place indeed so rapidly that, if the divided structures have come or have been brought into immediate contact, there may be firm adhesion at the end of twenty-four hours. This is primary union, or union by first intention, which, rare in the old days, commonly occurs in this era of aseptic surgery. The full sequence of events in these cases cannot, it is true, be well determined by continuous 32 Digitized by Microsoft® OH. IV IN VASCULAR AEEAS 33 microscopic examination ; but if the rabbit or dog be employed, and tissues, wounded in the manner described, be removed and examined at successive short intervals, we see that the changes which occur are mainly, nay, almost entirely, related to the pre-existing cells of the part. The section divides a certain number of capillaries ; but in the very act of division the divided walls are apparently brought together ; and, partly by this means, partly by contraction, the lumina of these minute vessels become occluded, and the hsemorrhage into the wound is altogether inconsiderable. Within an hour after the operation it is evident to the naked eye of a careful observer that the immediate neighbourhood of the wound is reddened and tumefied, but only slightly ; and, associ- ated with this, there is a feeble exudation between the opposed surfaces. But the exudation is not great, and even within this first hour after the infliction of the wound there may be development of fibrin, and coagula- tion of the exudate, leading to a provisional cicatrix cementing together the opposed surfaces. In this exuda- tion, and in the tissues in the immediate neighbourhood, the leucocytes that have undergone diapedesis may be few and far between, and may scarcely attract attention. The reaction, then, on the part of the vessels and of the leucocytes is of the slightest. At times the dilatation of the vessels is more considerable, and with this there is a fair amount of oozing into the wound of a thin serum, which has little tendency to coagulate. Thus it has not been an infrequent experience of surgeons that if an extensive skin-flap be sewn up completely the amount of serum accumulating between the surfaces of the wound during the next few hours causes not a little tension and discomfort. If one or two of the stitches are cut and this serum allowed to drain away the parts unite forth- with. It has become the practice to make allowance for D Digitized by Microsoft® 34 INFLAMMATION ft. i this serous oozing by not completely closing one end of such a wound, and inserting there temporarily a " drain " of sterilised gauze, so that this fluid escapes immediately and primary union is facilitated. Study of sections in these cases shows that the main part is played by the pre-existing cells of the part ; of these a certain number (not so many as might a priori be expected) are destroyed immediately, and show all the signs of disintegration ; a number relatively large have been injured only, their nuclei remaining intact, though their processes or some portions of the cell-bodies have been cut through. It is difficult to determine these injuries in the small cells of the cutaneous tissues ; they are better seen in the peritoneum when slight inflamma- tory changes have there been induced. It can, however, be made out that the cells in the immediate neighbour- hood of the wound become enlarged, and, without show- ing signs of division, prolong themselves (that is to say, send out prolongations) into the region of the provisional fibrinous cicatrix. In this way, before the end of the second day, there may be a more or less complete re- placement of the primary unorganised cementing sub- stance by organised growing tissue, — formed, in the first place, by the interlacing of processes from the neighbour- ing cells ; in the second, and later, by a multiplication of these cells, together with a development of new capil- laries, few in number, which branch off from the slightly congested vessels in the neighbourhood. Thus in this case the process of repair is characteristically associated with hypertrophy and the new growth of the fixed cells of the tissue ; while vascular changes, exudation, and leucocytosis are relatively little marked. I have, how- ever, never come across a case in which they have been entirely absent, save when the section has been truly extra-\'ascular — that is to say, when it has not penetrated Digitized by Microsoft® CH. IV IN VASCULAE AEEAS 35 into the vascular region of the skin, and has affected only the epidermis and outermost layers of the dermis. In such cases the response to injury may show itself purely as a proliferation of the epithelial cells. As I have said, observations of this nature labour under the disadvantage that they must of necessity be discontinuous. I bring them in at this point, inasmuch as they represent the mildest condition of the inflammatory reaction. I have not personally observed this series of changes in tissues which permit of continued study under aseptic conditions ; neither am I acquainted with any observa- tions wholly fulfilling these conditions — made, that is to say, upon transparent vascular tissues subjected to the mildest aseptic injury and examined continuously under the microscope. (ii.) The response to injury in the cases just mentioned was of the slightest. Let us now pass on to cases in which it becomes more pronounced ; and in order to continue the comparative study of inflammation I would first describe the series of events in a highly vascular and transparent region in a low vertebrate animal, namely, in the tadpole's tail. If this be injured, either by the application of a caustic or by the introduction of a foreign inert body, into its substance, a definite advance upon what was recognisable in the case of the axolotl, for example, is to be made out. Here the tail is very vascular, the wandering cells in the connective tissue are very few in number, while the blood is fairly rich in leucocytes, which are small relatively to the size of the vessels. The results of injury are a congestion of the vessels, noticeable within fifteen minutes, and a well- marked determination of leucocytes to the injured region. These cells, in the main, pass out from the vessels ; the few leucocytes pre-existing in the tissue appear to play a very small part. Compared with the axolotl experiment Digitized by Microsoft® 36 INFLAMMATION pt. i this observation is of considerable interest. Instead of a slight reaction sloiuly developing there is a rapid reaction ; instead of a slight accumulation of leucocytes there is a most pronounced accumulation. If there be any meaning in the determination of leucocytes to the region of injury, then evidently the active participation of the vessels of that region in the reactive process is fraught with benefit — it is a further important factor developed with the development and advance of the organism. The fuller details of this vascular interference in the inflammatory process have been followed by many observers, among whom first and foremost was Cohn- heim (28), and to this end the frog has supplied the most convenient means in regions at once vascular and fairly transparent, such as the web of the hind feet, the tongue, and the mesentery. Other observers passing higher in the scale of vertebrates have employed the mesentery of the cat, dog, and other mammalia. Suffice it to say that, with slight modifications due to local conditions in the tissue examined rather than to the animal selected, the process has been found to present the same features throughout the whole of the adult vertebrata, from the reptilia upwards. For general examination, perhaps, the best and simplest method of observing the succession of changes that follow injury of a vascular area is to be found in Coats' modification of Cohnheim's original experiment upon the frog's web (30). In order to reproduce as nearly as possible the conditions of an early wound, instead of employing a caustic or chemical irritant, a small portion of the cutaneous surface is nipped off — the section being just deep enough to pass through the cutaneous layers without causing haemorrhage. For the experiment to proceed satisfactorily, it is necessary that the frog be curarised after having been pithed. The web of a small frog is so thin that the changes Digitized by Microsoft® CH. IV IN VASCULAE AEEAS 37 occurring in and around the vessels of the part can readily be followed even with a high power of the microscope. The first change noticeable in the immediate neighbour- hood of the injured membrane is a dilatation of the vessels, first of the arterioles (although this may be very slight), and then of the veins ; and in this first phase there is a very evident acceleration of the blood-flow. At this early period the capillaries show little evidence of dilatation, but in the course of an hour expansion is readily distinguishable, and sundry capillary channels, previously invisible, become occupied by blood and show themselves. This first stage lasts for an hour, or in some cases perhaps two, and is followed by a phase of slowing of the blood-current. While previously a well-marked axial stream of corpuscles had been evident, with a peripheral zone of plasma devoid of corpuscles, the former now broadens out, the latter becomes less and less, and as it narrows increasing nuhibers of the clearer rounded haemal leucocytes are to be seen in it ti'avel- ling at a slower rate than the more axial stream, and every now and then stopping beside the walls of the vessels, and after a short stoppage passing on again. The leucocytes conduct themselves as if they have become "sticky."^ As pointed out by Wells (31), it is eminently probable that the diffusible noxa causes modification of the surface tension of the endothelium, and it may also be of the leucocytes, and that the sbickiness is due to this cause. We see the first signs'of margination. Lister demonstrated long years ago that ^ Even so low down in the scale as Daplmia this same peculiarity is noticeable : there in health, as Mr. Hardy (23) has pointed out, the leucocytes move freely ; hut, if the slightest injury be inflicted upon the carapace, the leucocytes, previously unadliesive, soon show the tendency to adhere to the walls of the body-cavity beneath the region of injury and elsewhere. Digitized by Microsoft® 38 INFLAMMATION PT. I the red corpuscles also manifest an increased viscidity, which again is a factor in the slowing of the blood stream. As the current becomes yet slower all distinction between axial and peripheral streams is lost ; the cor- FiG. 4. — Intlamed raysentery of frog to show iiimgination of leueocjtes in the dilated capillaries (a) ; migration of leucocytes (ft) ; escape of red corpuscles (c) ; accumu- lation of leucocytes outside the capillaries (d). — After Ribbert. puscles, closely packed together, fill the whole lumen ; the leucocytes in increasing number approach the vessel- walls ; they adhere more firmly, and so long as a current is recognisable the action of the stream leads them to assume a pear-shaped appearance, the rounded ends pointing in the direction of the current. As the stream slows gradually the corpuscles may at last move in a series of jerks synchronous with the beats Digitized by Microsoft® CH. IV IN VASCULAE AEEAS 39 of. the heart ; or frequently in the veins and capillaries the mass of blood may be seen moving slowly first in one direction, then in the other. Frequently one or other of these stages is followed by complete stagnation, or stasis, of the blood in the vessels of the injured area — I say frequently, for at other times little or no absolute arrest is seen in the vessels. Accompanying this stage, although observers employing other and chemical methods of inflicting injury have in general omitted to call attention to the fact, there is already a considerable oozing or exudation of clear fluid from the wound ; there is, that is to say, an outpouring of lymph, and this apparently from the distended vessels. Now, with the slowing of the stream the leucocytes, accumulated next to the walls of the small veins and within the capillaries, pass from the interior to the exterior of these vessels ; and, if the process be studied carefully with a higher power, it can be seen that this mode of passage is of an active, or apparently active nature.^ A series of leucocytes can be distinguished, some of which are rounded or flattened, in immediate contact with the wall of the vein ; others possess a prolongation passing into the wall ; in others, again (or in the former if they be watched in the fresh specimen), the prolongation enlarges on the outer side of the small vessel while the portion of the leucocyte within the vessel becomes smaller. The final phase of this act of migration is that the whole leucocyte passes through, and is found in the lymph- spaces around the vessel-wall. This process of migration may be so general that in the course of five or six hours all the small veins of the region show a crowd of leucocytes situated along their outer surface. With these ' The process can be fully made out if at this stage the wounded region be removed, fixed immediately in weak osmic acid, and prepared for examination by the higher powers of the microscope. Digitized by Microsoft® 40 INFLAMMATION pt. i a greater or smaller number of red corpuscles may also make their escape. In this modification of Cohnheim's experiment a further stage is to be recognised. While at first the fluid exuded from the cut surface was clear and relatively free from cells and cell-debris, now, as the inflammatory process continues, an increasing number of leucocytes is contained in the exudate. The leucocytes do not remain in the immediate neighbourhood of the vessels, but many of them pass on to the injured surface; still, it would seem, by active amceboid movement. Thus at the end of six hours this surface may be covered by a serum or fluid containing large numbers of these leucocytes. Here then we have the first step towards the formation of a scab or provisional protective covering to the wound. Further observations cannot well be carried out in the pithed and curarised frog; but if an unpithed, non- curarised animal be taken, and the observations upon the earlier stage be neglected, it can be made out that if irritant matter do not find entry into the wound the process may be arrested at this point ; the leucocytes upon the surface may break down, and with their breaking down and the formation of fibrin a soft scab be formed : the stasis of the blood in the distended vessels may be followed by a re-establishment of the current and slow return of the vessels to their former calibre, while beneath the thin, soft scab the epithelial cells rapidly proliferate. Within twenty -four hours there may be abundant evidence of this new growth of the epithelium tending to encroach upon and cover the wound ; and not merely of new growth, but also of dis- placement and movements of the healthy cells at the edge of the skin wound towards and over the bared surface. At the same time the region becomes less and less populated with leucocytes, so that — not to enter Digitized by Microsoft® CH. IV IN VASCULAE AEEAS 41 fully at this point into the reparative process — within sixty hours the region may show little sign of the injury and consequent inflammation. (iii.) On the other hand, if irritants of a microbic nature enter the wound the process may extend, as in inflammation of the cornea. More especially if the water in which the frog is kept become foul, there is a tendency in the inflammatory processes to spread, and in the cells, both fixed and migrated, of the central area to break down, leading to the formation of a spreading ulcer. The steps of this sequence of affairs it is difficult to follow by continuous microscopic examination, partly on account of the increased opacity of the region, partly because the process extends over days rather than hours. Here, therefore, I merely mention this possible extension of the change with its main naked-eye appearances. It is not possible by continuous observation to make out the steps of this more extensive inflammation characterised by excessive emigration of leucocytes and destruction of these together with the fixed cells of the tissue — the pyogenetic inflammation. Several observers, however, have followed its successive stages by means of examination of affected tissues at successive intervals after the infliction of injury. Digitized by Microsoft® CHAPTEE V THE EXPERIMENTAL PRODUCTION OF SUPPURATIVE INFLAMMATION While, as shown by Councilman (32), Grawitz and de Bary (33), Steinhaus, Leber, and others (34), a sup- purative inflammation may, under certain conditions, be brought about experimentally by the action of chemical irritants, such as mercury and turpentine ; yet under ordinary pathogenetic conditions suppuration is indiiced by the growth of micro-organisms within the tissues. Hence it is better to study the conditions as induced by the inoculation of pus -producing microbes into one or other tissue. A very full series of observations upon the development of abscesses through the agency of the Staphylococcus pyogenes aureus has been made by Hohnfeldt (35). He inoculated small quantities of pure cultures of the microbe subcutaneously into rabbits. Four Jwurs after inoculation the vessels of the region were found densely filled with corpuscles, and in them a commencing margination of the white corpuscles was discernible. Leucocytes were present within the tissue in numbers greater than normal ; although, compared with later stages, they were infrequent. They were of two kinds — the mononuclear in the majority, the poly- morphonuclear ^ in lesser numbers ; both forms were ' This term while precise is painfully sescjuipedaliau. For myself I 42 Digitized by Microsoft® OH. V PEODUCTION OF SUPPUEATIVE 43 congregated mainly around the line of entrance of the injecting needle. Many of the connective-tissue cells were so swollen as to be rounded rather than flattened. The injected cocci, lying in the lymph-spaces, were scattered through the tissue ; in part free, in part already ingested by cells, not only by the leucocytes, but also by connective-tissue cells, the number within leucocytes being not inconsiderable. Preparations made at the end of ten hours showed the same conditions, but more distinctly. There was ample evidence of migration of the leucocytes, margination in the congested vessels, various stages of passage through the vascular walls, and large collections of the cells in the perivascular lymph- spaces ; from these they spread into the spaces between the bundles of connective-tissue fibrils. The cocci lay in the lymph-spaces in increased numbers, and the massing of leucocytes corresponded in position to the accumulation of microbes. In these regions the leuco- cytes were mainly polymorphonuclear, but in the boundary zone away from the cocci the mononuclear form predominated. At the end of twenty hoicrs there was further accentuation of these conditions. As yet an abscess proper had not formed, but there were enormous numbers of leucocytes and also of micrococci ; the fibrillse of connective tissue were widely separated by the collections of leucocytes, which clustered round and hid the connective-tissue cells. With the completion of forty-eight hours a well-defined abscess had formed, separated sharply from the surrounding healthy tissue. The centre of the abscess was seen to consist of densely- pftcked leucocytes mingled with large growths of cocci. These leucocytes were almost entirely polymorpho- am willing to see it replaced by the ea.v]ieT polymiclear, provided it be kept in mind that so used polynucUar is an abbreviation and not the synonym for muUmuelear. Digitized by Microsoft® 44 INFLAMMATION pt. i nuclear ; and in this central area the nuclei of some showed fragmentation. Such accumulations of living and dead leucocytes in fluid matrix constitute pus. Neither leucocytes nor connective-tissue cells showed the slightest indication of mitosis. In the central area all traces of the previous capillaries had disappeared ; in the peri- pheral zone they were easily recognisable, being fully injected and showing a marginal disposition of their leucocytes, many of which could be seen (in osmic acid preparations) fixed in the process of migration. The majority of the cocci lay in these leucocytes. Even where the colonies of the microbes were thickest there the majority were intracellular. Passing towards the periphery the number of cocci became smaller and smaller. At the periphery they could be seen not only to be intracellular, but also free in the lymph- spaces ; and Hohnfeldt, with other observers, saw them definitely grouped within the endothelial cells of the peripheral vessels. Thus it may be noted that at this stage the proliferating microbes extended into the healthy tissues outside the abscess. In the centre of the abscess the original tissue had wholly disappeared ; nearer the periphery light streaks and bundles of the disintegrating fibrillse could be recognised between the leucocytes. Not till about the tenth day did new growth of tissue begin to show itself During the preceding six days there had been more breaking down of the poly- morphonuclear cells, characterised by fragmentation of the nuclei and by fatty degeneration of the cell- substance. But by the tenth day the periphery had begun to assume the appearance of granulation tissue; it contained numerous capillaries and new-formed connective tissue with characteristic epithelioid cells or fibroblasts possessing large, oval, pale-staining nuclei. In these cells, as in the connective-tissue cells of the Digitized by Microsoft® CH. V PEODUCTION OF SUPPUEATIVE 45 surrounding healthy tissue, the numerous steps of indirect cell-division could be made out. In this granu- lation tissue cocci were absent and leucocytes were in- frequent. In the soft, cheesy, central area masses of cocci were still present. Whether these were living or dead, Hohnfeldt did not determine ; he inferred (what has since been proved by several observers to be an unsafe inference) that inasmuch as they stained well with aniline dyes they were alive. Thus, to sum up Hohnfeldt's observations, the pro- cesses occurring in a suppurative inflammation that ends in healing are the following : — 1. Primary multiplication of the pyogenic organisms with no immediate reaction. 2. Congestion of the region of invasion, with margiua- tion of the leucocytes ; signs of degenerative changes in the tissue cells of the region. 3. 'Collection, in the region, of mononuclear leuco- cytes ; then immigration of polymorphonuclear leuco- cytes ; multiplication of the cocci. 4. Ingestion of large numbers of the microbes by the polymorphonuclear leucocytes and other cells, including the endothelial cells of the vessel-walls. 0. Increasing immigration of leucocytes until the tissue becomes densely packed. This is accompanied by a yet greater proliferation of the microbes, which extend {i.e. are carried by lymph-streams or by cells) into the region outside the developing abscess. 6. Coincident destruction of the tissue of the affected part. 7. Degeneration of the leucocytes within what is now the sharply defined abscess. 8. Eventual proliferation of the connective tissue at the periphery of the abscess ; formation of fibroblasts in the highly vascular surrounding zone ; absorption. Digitized by Microsoft® 46 INFLAMMATION pt. i cicatrisation, and encapsulation of the debris of the leucocytes and micrococci. There are not a few points in connexion with these observations of Hohnfeldt that deserve discussion ; very possibly he has misinterpreted certain of the appearances. On the whole, however, he draws a full and accurate picture of the successive stages of suppurative inflamma- tion, and I may defer discussion to a later review of the action of the leucocytes and of the formation of fibrous tissue respectively. However, before leaving this general description of the series of anatomical changes induced by injury, there is another phase of the inflammatory process set up by pathogenic micro-organisms which must not be passed over— I refer to those cases in which, instead of ending in repair, there is extension and generalised disease. The stages preceding extension vary with the nature of the microbe ; thus, in some cases, the reaction to the invasion of the microbe is mainly leucocytic (as with inoculations of the micrococci of suppuration), in others it is mainly exudative or serous, the congestion of the vessels being followed by abundant exudation of serum into the tissues. This is the case in inoculation of animals — such as rabbits, guinea-pigs, and fowls — with cultures of micro- organisms which are peculiarly virulent in their behaviour towards these animals. Such a serous or exudative inflammation is, for instance, well seen if the vibrio Metchnikovi be inoculated into the pectoral muscles of a fowl. Within twelve hours, it may be, the seat of inoculation becomes greatly swollen, and on section is found reddened and congested ; while from it drains an abundance of relatively clear, faintly reddish serum containing but few leucocytes. In such a case as this the micro-organisms appear to pass with ease from the centre of infection into the Digitized by Microsoft® cH. V PEODUCTION OF SUPPUEATIVE 47 surrounding tissues, and thence into the lymphatics and general circulation, whence they may be obtained within twenty-four hours. Where there has been a well-marked abscess - formation in the region of invasion there, as already indicated, it is true that the microbes may be found outside the abscess at a fairly early period ; but in the main, proliferation is limited to the abscess, and the blood remains free and sterile. Under certain conditions of greater virulence of the pyogenic microbes it is found that as the abscess extends it becomes ill-defined — there is no sharp demarcation between the collected leucocytes and the surrounding tissue ; the columns of leucocytes spread ' indefinitely from the centre, and numerous micro- cocci are intermingled with them. Where this is the case there is a marked tendency for the microbes to find their way into the general circulation from this irregular peripheral extension along the lymphatic spaces, and to set up a condition of septicaemia as in the more serous inflammation described above. Septicmmia, or the passage of micro-organisms into the blood,^ with all the results of such a passage — the condition which sundry French observers have described as inflammation of the blood — we shall not discuss here. In septicaemia we pass beyond the local response to injury, we deal with a state of general systemic dis- turbance. Nevertheless certain phases of the septicEemic condition throw light upon the inflammatory process. In the first place, it is of interest to note that when the infective micro-organisms and their products are within the vessels they fail to induce the cardinal symp- toms of inflammation. They do not lead to exudation "■ This is the sense in which the term Septiccemia is employed by patho- logists ami bacteriologists ; by some surgical ■writers the word is employed as synonymous with Toxcemia ; to avoid confusion there is now a tendency to use the more precise term Bacterieemia to indicate the presence of microbes in the blood. Digitized by Microsoft® 48 INFLAMMATION vt. i of fluid from the blood or to widespread diapedesis of leucocytes. The stimulus, whatever it be, which leads to these phenomena at the point of invasion is no longer called into activity when the noxa is within the circu- latory apparatus. This is the reverse of what might be expected were the inflammatory process primarily due to a modification of the endothelium of the vessel-walls by the irritant, a modification passively permitting the exudation and passage outwards of the leucocytes. This statement that infective micro-organisms and their products circulating within the blood fail to induce inflam- matory changes, would seem to need modification when the development of metastatic abscesses is taken into account — of secondary abscesses, that is, in tissues at a distance, and not in direct continuity with the original focus. But a study of the mode of production of these abscesses shows that the statement still holds. Such abscesses originate round emboli of pyogenic micro-organisms in the capillaries. Sundry cocci are arrested in a capillary, proliferate, and fill the vessel. It must not be thought that the plugging or embolism is an immediate process in these cases — that the bacteria are present in the blood in such numbers that a cluster of them, passing into a capillary, blocks it. Experience shows that, with a bacterisemia of this extent, death ensues so swiftly that there is no time for abscess -formation. Either the bacteria are contained in a small mass of infected blood- clot, which is the immediate cause of the blockage (as, for example, in abscess of the kidney secondary to infective endocarditis, and in lung abscesses following upon suppurative thrombosis of the lateral sinus), or, in other cases, isolated bacteria passing with the blood into a capillary are taken up by a phagocytic endothelial cell, and, instead of being destroyed, multiply, lead to the death of that and surrounding cells, and form a colony Digitized by Microsoft® CH. V PEODUCTION OF SUPPUEATIVE 49 occluding the capillary. It is only when a minute vessel is thus occluded that the ahscess-process begins, that is to say, when by this occlusion the vessel has become extravascular ; and while it is true that, primarily, the arrest of pathogenic microbes within the capillaries is often associated with a small accumulation of intra- vascular leucocytes and with degenerative changes in the vascular endothelium, the metastatic abscess, as such, forms not by accumulation of leucocytes in the occluded vessel, but around it; the leucocytes migrating from surrounding capillaries. The Production of Suppurative Inflammation in Serous Cavities. — Certain important modifications of the process above described as occurring in abscess formation are to be observed when inflammation affects the highly vascular walls of serous cavities, such as the abdominal, the pleural, or the peritoneal. From the very vascularity of the affected layers there is, in the first place, a tendency to a relatively abundant exudate, and in the second, this exudate pouring into a large sac is apt to bring about the extension of the irritant over a wide surface. Thirdly, not only do we find leucocytic migration, but, in addition, the endothelium covering the serosa now plays an important role. If a moderately severe inflammation be set up by introducing a culture of the Bacillus coli into the abdominal cavity of the guinea-pig, then, as pointed out by Beattie (36), if samples of the inflammatory exudate be withdrawn at intervals, a definite increase in the polynuclears is recog- nisable in from one hour to two and a half hours, and in non-fatal cases the number becomes greater and greater, until from thirty to thirty-six hours have elapsed. In such non-fatal cases the number of these cells returns to the normal in about seven days. At from the eighteenth to the twenty- fourth hour a cell of a wholly different E Digitized by Microsoft® 50 INFLAMMATION vr. i type makes its appearance. Unlike the polynuclear leucocyte, the nucleus of this form is characteristically not lobate, but round or oval — round in the smaller cells of this type, and then deep staining with but little surrounding protoplasm ; oval and pale staining in the larger cells, and then surrounded by a large cell body, constituting the so-called " hyaline cell." As Eanvier showed (37), these cells are of endothelial origin, derived from the actively proliferating serous endothelium. From this period onwards these cells increase in number, until during the third day in non-fatal cases they greatly out- number the polynuclears, and may be still present up to the eighty -fourth hour, when the latter have almost completely disappeared. Reference will be made to these cells and their properties in the next chapter. Digitized by Microsoft® OHAPTEE VI THE GENERAL REACTION WHICH MAY ACCOMPANY INFLAMMATION In the second place, through this study of advancing inflammation it is of interest to trace the very close relationship that exists between inflammation and fever. Besides the local changes here described, local injury is accompanied by systemic disturbances. These may be slight or grave. Take, for instance, progressive abscess- formation, or follow the development of a malignant carbuncle in man. At first the reaction is purely local, but very soon, long before any of the micro-organisms are capable of detection in the blood, there is a raised temperature -and a slight febrile state, the fever becoming more and more evident as the local process becomes more and more extensive, until with the detection of the microbe in the blood the most severe fever, with con- stitutional disturbance, sets in. Local inflammation, then, without any other possible explanation than either the nervous irritation to which it may give rise, or the passage into the general circulation of the soluble products of bacterial growth and tissue -destruction, or both, may lead to the development of the febrile state. How large a share is played by these two possible factors it is diffieult to say. That bacterial products injected into the circulation lead to the rapid production of the 51 Digitized by Microsoft® 52 INFLAMMATION pt. i febrile state rests on ample evidence ; but whether these act directly by inducing increased cellular activity, or indirectly by stimulating the cerebral centres, we cannot absolutely say. As yet we have little accurate know- ledge of the part played by the nervous system in the development of the febrile state. This, however, may safely be declared, that the more we study the continued fevers of bacterial origin, the more do we discover that these commence by a local inflammatory disturbance. The continued fevers of bacterial origin are, in general the continuance, or rather the extension, of a primarily localised inflammatory lesion. This it may be noted is not necessarily the case with fevers of protozoal origin, caused, like malaria, by the introduction of the specific organisms into the circulating blood through the agency of puncture of subcutaneous capillaries by insects that " sting." The sting of such insects may, it is true, cause a local inflammation, but this bears no direct relationship to the multiplication of the infective microbe in the blood. In this conception of inflammation as essentially a local process we find ourselves at variance with Eibbert (38), whose views have been somewhat widely accepted among German pathologists. Eibbert holds that "in- flammation includes both local and general processes " {loc. cit. p. 11). He calls attention to the fever which may supervene in the course of inflammation, the active new formation of leucocytes, mainly from the bone marrow, and discharge of the same into the blood, whereby leucocytosis is set up, and to the increased development of bactericidal and anti-toxic substances in regions distant from the area of primary injury ; also to the various degenerative processes in distant organs — cloudy swelling, fatty degeneration, etc. — evidently due to the diffusion of toxie substances either from the inflamed area or from organised bodies, such as bacteria, which have escaped Digitized by Microsoft® CH. VI aENEEAL EEACTION 53 from the zone of active inflammation. But at tlie same time he admits (1) that these general processes can be induced experimentally without there being any local disturbance, as also that (2) mild grades of inflammation may lead to no general involvement of the system. He acknowledges thus that the two are not inevitably and essentially united. The logical outcome of such an inclusion of the general body disturbances into our conception of inflam- mation leads to a lack of anything like a boundary between the condition of inflammation and that series of general disturbances which for want of a better term we speak of as (general) infection. According to Eibbert, inflammation must be made to include infection. We see no " must " in the case ; on the contrary, and we gravely doubt the wisdom of such teaching. One might as well banish wholly the idea of inflammation as a distinct entity. It appears to us both more sensible and more in accordance with tradition to hold that (1) inflammation is the local reaction to injury, (2) that this may or may not be accompanied or followed by systemic reaction, and (3) that this systemic reaction to injury covers so wide a field, including not only the discussion of fever, leucocytosis, anti- toxic formation, and the principles of immunity, but also (as Eibbert neglects to note) that of pain and shock, that advisedly it should be considered apart and then in several chapters. That in studying the phases of the local reaction we must repeatedly advert to the systemic reaction is one thing ; it is another thing to regard systemic reaction as an essential part of the process. Digitized by Microsoft® CHAP TEE VII SUMMARY OF THE FACTS THUS FAK BKOUGHT FORWARD The main facts gathered thus far concerning the inflammatory process, and the conclusions to be drawn therefrom, may now be placed in order before I discuss in detail the various factors in the process. They are — 1. Injury, when it is not so widespread and severe as to lead to the death of the individual, is followed by a reaction on the part of the organism. This reaction may be (a) localised, (6) generalised ; it is the first of these that constitutes inflammation. 2. In unicellular organisms the continued vitality of the iirdividual after injury, and in multicellular organisms the vitality of the individual cells, is dependent primarily upon the persistence of the nucleus ; if this be destroyed or removed, the rest of the cell is incapable of complete restitution and continued growth. 3. In unicellular organisms the reactive process is twofold, and consists of («) destruction or removal of the irritant ; destruction being brought about by a process of intracellular digestion, removal by extrusion of the irritant ; (6) new growth of the organism. 4. This response to injury on the part of unicellular organisms is essentially reparative. 5. In multicellular organisms, with division of labour among the constituent cells of the individual, there is a 54 Digitized by Microsoft® cHvii SUMMAKY OF FACTS 55 separation of functions ; the twofold local reaction to local injury is yet more clearly marked ; but (a) The destruction or removal of the irritant is in the main accomplished by the wandering cells of meso- blastic origin. (h) The new growth to replace the tissue destroyed by the irritant proceeds in the main from the fixed cells of the tissue. 6. Ascending the scale of multicellular organisms, a division of labour and differentiation of function is discoverable among the wandering raesoblastic cells. Whereas in the lower forms of the Metazoa one form of leucocyte alone is present, in the higher forms two or more varieties can be distinguished which possess different properties and act differently towards irritants introduced into the system. 7. According to the nature of the irritant causing the injury, the leucocytes are actively attracted in greater or less numbers to the region of injury, surround the irritant, and remove or destroy it by means very similar to those employed by unicellular organisms. Where the irritant is present in the form of discrete particles, some at least of the leucocytes may incorporate the particles, and remove them or destroy them by a process of digestion. Others of the leucocytes in the higher Metazoa do not act thus as phagocytes ; never- theless they are equally attracted to the focus of inflammation, and presumably tend to counteract the irritant by some other (extracellular) means. 8. While to the wandering cells appears to be allotted the main duty of removing deleterious and irritant matters, certain of the fixed cells of the organism, notably the endothelial cells of the vessels, also exert these functions. 9. Among the very large number of Metazoan forms Digitized by Microsoft® 56 INFLAMMATION ft. i in M'hich no complete vascular system is present, this attraction of the leucocytes to the region of injury is at first the sole recognisable response to injury proliferation of the fixed cells occurring in the neighbourhood of the injuiy at a later period. The relation between leucocytic migration and tissue proliferation is, however, a variable quantity ; there may be active proliferation in response to injury with little evidence of wandering in of leuco- cytes. 10. Among the higher Metazoa, in which there is a well-developed vascular system, the determination of leucocytes to the region of irritation still continues, nay, more, is markedly aided by the participation of the vessels in the inflammatory process. 11. The vascular phenomena in inflammation may be regarded as serving two main purposes — (a) the pouring out of increased fluid into the injured area ; (&) the afilux and migration of leucocytes. 12. Even in the highest Metazoa, possessing fully developed vascular systems, the response to injury in a non-vascular area, such as the cornea, may be associated with no change in the surrounding vascular areas, but purely with a determination to the injured area of leuco- cytes already free in the surrounding tissues. 13. The second phase of the inflammatory process, that of tissue -repair, but very rarely occurs without evidence of previous migration of leucocytes and exudation from the congested vessels ; nevertheless with certain mild grades of injury it can occur. 14. A comparative study leads inevitably to the con- clusion that the determination of leucocytes to the region of injury is the most constant and most characteristic early response to injury recognisable throughout the Metazoa, and that it must be regarded as the most important factor in the first stage of the inflammatory Digitized by Microsoft® CH. VII SUMMAEY OF FACTS 57 process. The vascular phenomena noticeable in the higher Metazoa must be regarded as a second and highly important adjuvant factor of later development. New tissue -formation is the prominent characteristic of the later stages of the process. 15. As among the Protozoa, so in the Metazoa, the response to injury is consistently in the direction of repair of injury. This general survey of the response to injury through- out the animal kingdom demonstrates most clearly that the same broad principles, the same methods of defence and repair on the part of the organism, are called into activity from the lowliest forms to the highest ; that, in fact, no line can be drawn to separate one set of phenomena as truly inflammatory from another set which, while also a response to injury, is non-inflammatory. Although it is true that the term inflammation implies a reddening and congestion of the vessels, we find upon closer examina- tion that reddening and congestion are not the funda- mental but superadded features in the process of repair of injury — features superadded as the organism advances in its place in the animal kingdom. Thus if we are to comprehend the process satisfactorily, we must pass beyond the narrower acceptation of the term. Having thus sketched broadly the general phenomena of the inflammatory process, it will be well now to describe in fuller detail the factors of this process among the higher vertebrata, and to bring together the more import- ant results of the study of the respective functions of the wandering cells, the vessels, the fixed cells, and the nervous system in inflammation. Digitized by Microsoft® Digitized by Microsoft® PAET II THE FACTOES IN THE INFLAMMATOEY PEOCESS 59 Digitized by Microsoft® Digitized by Microsoft® I. — THE PART PLAYED BY THE LEUCOCYTES CHAPTER VIII THE VARIETIES AND CLASSIFICATION OF THE LEUCOCYTES As I have already shown, there is more than one form of leucocyte in the mammalian organism, and these several forms evidently possess different attributes, and act differently in the reaction to injury. Inasmuch as they have been variously classified — so variously, in fact, that it is often far from easy to collate the various descrip- tions and to discuss the forms distinguished by one observer in the terms of another — -it is necessary to give the chief classifications of them and their relations. The first to discriminate between the forms of white corpuscles in the blood was Wharton Jones (39) so long ago as 1846. He drew a distinction between A. Granule cells — Finely and coarsely granular. B. " Nucleated " cells — Non-granular. These observations were confirmed and advanced by Max Schultze (40), who made out the following forms : — 1. Small round cells with round nucleus and little clear proto- plasm. 2. Larger cells with round nucleus and more clear protoplasm. 3. Cells with finely granular protoplasm, and one, two, or more nuclei. 4. Cells with coarse granules in the protoplasm. 61 Digitized by Microsoft® 62 INFLAMMATION pt. n The distinctions drawn were, so far, purely morpho- logical ; and very little notice was taken of these varieties for a long period until Ehrlich (41), in a notable series of papers extending from 1878 to 1887, drew attention to the fact that the wandering cells of the organism react diversely towards the different aniline dyes, and possess diverse tinctorial affinities indicating chemical differences in the nature of certain constituents of the cell bodies. The granules of the previous observers were found to be variously affected by the dyes employed ; they were shown not to be fatty, but — as Ehrlich put it — of the nature of a glandular excretion ; ^ and comparing the effects of the two groups of aniline colours — that in which the dye is associated with the acid constituent of the salt and that wherein the dye forms the base (the " acid " and " basic " aniline dyes respectively) — he made out the existence of five forms of granulation associated with as many varieties of wandering cells. His table of cells, according to their granulation, is as follows : — a. granulation — Eosinophil — Cells frequent in horse's blood, present constantly in small numbers in liuman blood ; numerous in medulla of bones of rabbits, dogs, guinea- pigs, etc. Stain deeply with acid aniline dyes. Granules large and coarse. /3. granulation — Amphophil — Cells frequent in rabbits and guinea-pigs in blood ; present also in medulla of bones. Stain both with acid and basic dyes. Granules iine. y. granulation — Basophil — Large cells found in the con- nective tissue, from the frog upwards, " Mastzellen " ; in blood of man only in certain cases of leukasmia. Stain only with basic dyes. Granules coarse. S. granulation — Fine Basophil — The "mononuclear" leucocyte of human blood. Granulation fine. Stain with basic dyes. ' J. Weiss has studied the micro-chemical reactions of the eosinophilous granules, and concludes that they are of albuminoid nature ; since they were found not to be digested in gastric juice, he would ally them with the nueleins. Digitized by Microsoft® CH. viii VAEIETIES OF LEUCOCYTES 63 c. granulation — Neutrophil — The most frequent leucocyte of human blood, polymorphonuclear or " polynuclear." Stain only in neutral dyes — not in acid or basic. Ehrlich and his pupils and Eieder (42) have done much to throw light upon the relative numbers of the leucocytes possessing these different granulations in different diseases, but at first they accomplished little in discovering the origin of the various forms, their functions, or their relationships. We owe the first satisfactory studies upon the properties to the long- continued and wonderful series of researches upon Phagocytosis initiated by Metchnikoff, who made out that the different wandering cells of the body act differently towards microbic and other foreign particles introduced into the organisms. Thus he was led to draw a distinction between — 1. Lymphocytes — immature leucocytes. 2. Large hyaline cells, mononuclear, phagocytic, " macrophages." 3. Smaller neutrophil cells, polynuclear, " microphages." 4. Eosinophil leucocytes — very rarely phagocytic. English observers, notably Professor Sherrington (43), the late Dr. Kanthack (44) and Mr. Hardy (45), and more recently, following these. Dr. Durham (46), Pro- fessor Muir, and Dr. Beattie (36), have made notable advances in the determination of the function of the wandering cells in inflammatory and other conditions. Of American observers. Dr. A. E. Taylor (47) deserves special mention. Kanthack and Hardy have materially simplified the classification given by Ehrlich by dividing the leucocytes of the blood into : — „■ _. T , } Oxyphil cells. Staining with acid dyes. 2. Finely granular j ,' _. 1 , !• Basophil cells. Staining with basic dyes. 4. Finely granular ] ^ o j 5. Lymphocytes. 6. Hyaline cells. Digitized by Microsoft® 64 INFLAMMATION Their coarsely granular oxyphil cells are the eosino- phil cells of most writers ; their finely granular are the neutrophil and amphophil of Ehrlich. They prove conclusively that Ehrlich's neutral stain is in no sense to be regarded as such, but must be considered as a weak acid dye. Collation of the Classifications of H.s;matogenods Ledcocytes by Different Observers Kanthack and Hardy. Ehrlich. Metchnikoff. Durham. Finely granular oxyphil. Coarsely granular oxyphil. Finely granular basophil. Coarsely granular basophil. Lymphocyte. Hyaline cell. f Neutrophil cell. \ \ Amphophil cell. / Eosinophil. Basophil cell with 5 granulations. Mastzellen (7gran- ulations). Lymphocyte. Microphage. Eosinophil. Lymphocyte. Macrophage. Microxycyte. Macroxyoyte. Coarsely gran- ular basophil. Lymphocyte. /Hyaline cell. \^ Macrophage. In connexion with this subject of inflammation yet another classification must be entered into. The above forms are all to be found in the blood- stream in the inflamed tissue. We have to recognise also other wandering corpuscles which are not necessarily derived from the blood. It may be questioned whether it is right to speak of wandering cells of tissue origin as leucocytes, that term having first been employed as synonymous with white blood corpuscles, but on the old presumption that practically all the wandering cells seen in inflammation are derived from the blood, it has been customary to speak of all orders of these cells by this name, and certainly their characters are such as to render it difficult to distinguish them one from the Digitized by Microsoft® CH. viii VAEIETIES OF LEUCOCYTES 65 other save with care. Thus as a matter of custom and of practical utility we elect to speak of all these various cells indifferently as leucocytes.^ Thus further we may divide the leucocytes concerned in the inflammatory process into the three following groups : — 1. Hmmatogenous, viz. those derived from the blood- stream ; this includes polymorphonuclear (neutrophil and amphophil polynuclear) and eosinophil (coarsely granular oxyphil). 2. The histo-hcematogenous include the lymphocytes and hyaline cells and other cell forms apparently derived from the lymphocyte. All these may either have passed into the inflammatory focus from the blood -stream, or may be the result of proliferation of cells already within the tissue. 3. The histogenous cells originate locally as the result of local tissue proliferation, and not by passage into the parts from the blood-stream. The recent observations of Schridde (48), to which I shall refer later, indicate that improved methods of staining are capable of showing that there are distinc- tions to be made out between the lymphocytes of the blood and those of the perivascular sheaths, lymph glands, lymph follicles, and tissues in general. If this be so this class will largely disappear, and we shall be able to make a sharp separation between haematogenous lymphocytes on the one hand and histogenous on the other ; all that will be left in the histo-hsematogenous class being the hyaline cells of endothelial origin. ^ Some modern workers like Schridde are attempting to confine tlie term leucocyte purely to the granular cells of the blood, and make a distinction between leucocytes and lymphocytes, which appears to me to be indefensible. Digitized by Microsoft® CHAPTER IX THE DIFFERENT ORDERS OF LEUCOCYTES HyEMATOGENOUS LEUCOCYTES We need here say little regarding these, they are so fully discussed in all text-hooks of medicine and treatises upon the blood. We need but recall that the polymorpho- nuclear neutrophil cells are those which, passing from the blood, predominate in all cases of acute inflammation leading towards suppuration and abscess formation ; that in human blood, as in most mammals, the eosinophiles while very characteristic are generally rare, though they may be noticeably increased in number in certain diseases, notably where intestinal parasites, trichinae, etc., are present in the organism ; the mast cells are a still rarer form. While such cells may occasionally be found in the blood, we are personally doubtful as to whether those seen in inflammatory foci have wandered as such out of the blood- vessels. Their granules are large, and stain deeply with ordinary basic dyes such as methylene blue, and they must not be mistaken for small clusters of cocci. HISTO-H^MATOGENOUS LEUCOCYTES Here, as above noted, we have first to consider the lymphocyte and its modifications. It is now accepted by practically all workers that the lymphocyte seen within the tissues, and the small cell with round, deeply staining nucleus so large as almost completely to fill the cell, and Digitized by Microsoft® CH. IX HISTO-HiEMATOGENOUS LEUCOCYTES 67 having a scanty ring of surrounding cytoplasm, may be derived both from the blood-stream and by proliferation of the lymphoid cells normally present to a greater or lesser extent, more particularly in the sheaths of smaller veins. Until recently it has been regarded as impossible to make a distinction between these two groups of cells. Now Schridde (by his modification of Altmann's stain) makes out very definitely that granulation can be made Out in these cells, and that the granules of the haemal lymphocytes are of a wholly different type to those seen in the tissue lymphocytes and the cells of lymph follicles, and, basing himself — with Ehrlich — upon the fact that the granules of the different varieties of cells are constant features of the same and present constant characters, he concludes that here we have to deal with two distinct cell varieties. The granules of hsemal lymphocytes he declares are very small, and of about the size of those seen in neutrophil leucocytes, and by his method they take on a brownish red tint. Those of the peri-vascular lymphocytes are larger, few in number, and of a pronounced red colour. Plasma-Cells. — There is another form of mononuclear cell which must, we think, be included in this series, although, as to its properties and origin, there has been and still exists a very active controversy. This is the almost notorious plasma-cell. Unna (49) first named these in 1891, or rather misnamed them, using a term previously employed by Waldeyer for another form of cell. Unfortunately his description was not wholly adequate, and various later observers have evidently included and described under this term cells of more than one order, so that confusion is worse confounded. The cell which most closely conforms to Unna's descrip- tion, and which, therefore, I regard as the plasma-cell proper, has the following attributes : — it has a relatively Digitized by Microsoft® 68 INFLAMMATION pt. ii small, round or oval, not indented nucleus, coarsely granular, rich in chromatin and, further, staining darkly ; this nucleus is situated excentrically. The cell-body stains deeply with Unna's methylene blue ; the shape within the tissues is liable to considerable variation — often rounded or oval the cells may be polygonal or even drawn out into a spindle ; they are obscurely amoeboid. As to the possession of phagocytic properties, opinion is somewhat divided. The general agreement is that they are not seen to take up bacteria ; they may, however, contain inert particles of foreign matter such as vermilion or coal-pigment. As they grow larger and older, the cytoplasm tends to become somewhat vacuolated, and the nucleus to be less deeply stained. As to their eventual fate, nothing definite can be said at present. Cells having these characters are normally present in lymph-glands, spleen, and bone-marrow, and here every transition can be made out between them and the ordinary lymphocyte, which similarly, it may be noted, has a small, round, deeply-staining nucleus (even more deeply staining so as to appear homogeneous). Accord- ing to von Marschalko (50), they may be noted in any inflammation within twenty-four hours. More recent observers state that they do not appear in quantity within the zone of inflammation until several days have elapsed. Now, as noted by Justi (51) and Councilman (29), there is normally around the veins a lymphoid sheath, and in inflammatory conditions this sheath beconies noticeably augmented. The cells here multiply by direct division, and, in addition, here and there mitoses are visible (Justi). That lymphocytes are endowed with faint amoeboid activity (Wlassow and Sepp and A. Wolff (52)), and that, further, they migrate from the vessels, has now been pointed out by several observers (Councilman, Almkvist (53)). It is quite Digitized by Microsoft® OH. IX HISTO-H^MATOGENOUS LEUCOCYTES 69 possible, therefore, that the increase in the perivascular lymphoid sheath is in part due to migration from the vessels, and, therefore, that some at least of the hsemato- genous lymphocytes develop into plasma-cells. Though, admitting this, it seems to me evident that the majority of the plasma- cells are derived from the proliferating perivascular tissue, and thus are not immediately haemato- genous. It is on these grounds that I am led to include them here in order to emphasise the fact that not all the leucocytes seen in the field of inflammation are of vascular derivation. I have, I admit, here collated and selected out of a large number of very divergent descriptions those state- ments regarding the plasma-cell which conform with the conclusions I, personally, have reached regarding them. I am fully prepared to find that not all who have studied these cells will agree with what is here laid down, but to discuss the divergent views would occupy too much space. The reader, however, will find references to the leading papers bearing upon these cells given in the bibliography at the end of this study. The views here given in the main agree with those of von Marschalko, Paltauf (54), Justi, Mallory, and Councilman. In their properties the cells here indicated conform largely to Maximow's "polyblasts" (55), cells which Maximow regards as distinct from the plasma-cell. Maximow's very full and elaborate studies have deservedly attracted wide attention. The cells which he terms " polyblasts " are mononucleated amoeboid cells, having phagocytic properties, and, according to him, these may have more than one origin : (1) the majority he derives from migrated lymphocytes ; but (2) some he regards as of endothelial origin, derived from endothelial cells of perivascular lymph tissue, serous membranes, etc., which may have passed through Digitized by Microsoft® 70 INFLAMMATION the stage of being clasmatocytes (vide page 80); and (3) a small number he would derive from wandering cells, pre-existing in the tissues. He holds that all these cells may develop into large, somewhat actively amoeboid cells, as suggested by their irregular shape, Fig. 5. — Frum a case of acute interstitial nejjhritis (man), drawn by camera lucida, /.. Zeiss, ocular 2. Sliovving plasma-cells (1) in the interstitial tissue between tlie tubules. Tlie epithelium of the middle tubule (2) is degenerated ; the tubule con- tains polymorphonuclear leucocytes (3).— After Councilman. characterised by possessing a very definite centrosome situated close to the nucleus. I am inclined to think that Maximow's selection of tissues and of methods has led him to overlook the distinction between young lymphocytes and cells of endothelial origin. I cannot but think that had he studied the peritoneum, for example, he would have reached other conclusions. Digitized by Microsoft® CH. IX HISTO-H^MATOGENOUS LEUCOCYTES 71 The views here laid down are largely supported, though at the same time considerably extended by Schridde, using his new stains, which, it may be added, have the great advantage that by them it is possible to differentiate tinctorially the different forms of leucocytes present in the inflamed tissues. Schridde also sees every grade of development from the perivascular lymphocyte to the plasma-cell, though no relation betvi^een hsemal leucocytes and this form of cell. He, however, goes farther and finds three types of plasma-cells. The commonest of these is that with neutrophil granulations oi: weakly oxyphil. Barer are those with acidophil or oxyphil granules (in which the oxyphilic character is somewhat less pronounced than is the case with the ordinary eosinophils) ; while the rarest of all are those with metachromatic basophil granules corresponding to the mast-cells of the blood. We have thus, according to Schridde, two parallel series of cells — one derived in the main (in the adult) from the bone-marrow, thence gaining entrance into the blood ; the other derived from the perivascular and lymph-follicular lymphocytes. These results need confirmation ; I would only here say that, having seen Dr. Schridde's preparations and knowing his excellent technique, I am strongly inclined to accept his findings. Using a modified technique Beckton of Cambridge (56) confirms Schridde's observations so far as regards the existence of granules in lymphocytes and plasma-cells and their similarity. Hyaline Cells derived from the Vascular Endo- thelium. — We shall discuss these in connexion with histogenous leucocytes in general. Here we would only note that there is a certain amount of evidence that vascular endothelium can give origin to clear hyaline cells with little or no granulation. Digitized by Microsoft® CHAPTEK X THE DIFFERENT ORDERS OF LEUCOCYTES (continued) HISTOGENOUS LEUCOCYTES The part played by these is most clearly seen in the study of inflammation of the peritoneum. Many years ago Cornil and Eanvier (37) called attention to the very active proliferation of the endothelial cells of the great omentum in inflammations set up by the injection of dilute solutions of silver nitrate. They pointed out that these cells, flat and lamellar under ordinary conditions, become greatly enlarged with swollen nuclei which, within a few hours, undergo direct division, so that many cells come to possess two or three nuclei. Indirect division (mitosis) is only seen, according to Cornil and Toupet, in forty-eight hours. Some more recent observers have recognised it much earlier, Beattie (36) as early as the tenth hour. So swollen are the cells that they project prominently from the surface, being often pear-shaped and attached merely by a pedicle. As a result of the active proliferation, here and there large, semi-detached clumps of these cells may be made out. Cornil and Eanvier did not study the exudate ; this has been done by more recent observers, notably by Durham (46) and Beattie. The former, employing non-lethal intraperitoneal injections of several microbes, has described the same changes in the omentum as those described by Cornil and Eanvier, and has noted, more particularly, that these swollen cells 72 Digitized by Microsoft® OH.X HISTOGENOUS LEUCOCYTES 73 give origin, by direct division, to large, clear, mononuclear cells or leucocytes. These may be derived from the peritoneum generally, but the omentum is especially active in this respect. He identifies these cells with Metchnikoffs " macrophages," and Beattie has made a full study of the same. They are, according to him, the most characteristic form of leucocyte seen in peritoneal inflammation. After non-fatal peritoneal injection of the B. coli in the guinea-pig, he first observed an increase in the polymorphonuclear cells of the peritoneal fluid, which begins three hours after the injection and reaches its maximum in from six to thirty hours. Mononuclear leucocytes are first seen to increase in number about the eighth hour. On an average these are in numbers equal to or even greater than are the polymorphonuclears. From now onwards (in non-fatal as distinguished from fatal cases) they definitely pre- ponderate. As during the next two days resolution proceeds, the polymorphonuclears become fewer and fewer until the few cells present in the exudate are almost entirely mononuclear. These mononuclear cells (the hyaline cells of the late Prof. Kanthack and Mr. Hardy, and of other observers) vary in size. According to Beattie there is every transition from small cells resembling lymphocytes with a round or kidney-shaped nucleus rich in chromatin, and with scanty protoplasm up to cells four or five times as large, having a rounded or kidney-shaped nucleus which does not stain nearly as deeply as that of the smaller forms, but shows deeply- staining nodes of chromatin in the nuclear network. These larger cells have abundant cytoplasm, often showing extensive, fine vacuolation. In these respects the cells are identical with the swollen endothelial cells of the omentum. Nor are they merely passive agents — cells cast off in a moribund condition from the inflamed Digitized by Microsoft® 74 INFLAMMATION i-t. h peritoneum and undergoing degeneration. They are phagocytic ; they take up bacteria, though, in this respect, they are not, with certain exceptions, so active as are the polymorphonuclears. Thus, if tubercle bacilli be injected, they are found, in a few hours, almost exclusively within the mononuclear cells and not in the polymorphonuclears. This is in harmony with our general experience that polymorphonuclear leucocytes, while not negatively chemiotactic to tubercle bacilli, are not potently attracted thereto, so that these more leisurely mononuclears have the opportunity to take them up. What is most characteristic is that these mononuclear cells are active cellular phagocytes ; they take up other cells of the exudate — polymorphonuclears, eosinophils, and red blood-corpuscles. A single large mononuclear cell of a peritonitic exudate may often be seen containing three or four other cells or the remains of the same. There can, therefore, be no doubt that, in peritoneal inflammation at least, an important series of free cells or leucocytes is of endothelial or tissue origin ; the question is whether all these mononuclear cells are of like development. While clearly the larger forms are indis- tinguishable from the swollen cells of the peritoneal endothelium, and while the time of their appearance in the exudate coincides closely with the onset of active proliferation of that endothelium, we have the apparently contradictory statement that every transition is also to be observed between them and small lymphocytes ; while other observers studying lymphocytes proper are equally convinced that these cells never develop into the large hyaline cells above described. Now lymphocytes proper may be found in the peritoneal exudate. These apparently contradictory results may be harmonised by pointing out that, in the first place, in the very earliest Digitized by Microsoft® cii. X HISTOGENOUS LEUCOCYTES 75 stages, most cells are indistinguishable, and that, in the second place, a distinction can frequently be made out between the lymphocyte proper and the embryonic cell of endothelial origin. The former has a deeply-staining, rounded nucleus ; the latter a nucleus which, while also deeply staining, tends to be indented. There is, however, another difficulty ; if the omentum be examined during the period of peritoneal intiammation, its vessels are seen to contain mononuclear cells which, like these " hyaline " cells of the exudate, are devoid or almost devoid of granulation, and these intravascular cells are not to be distinguished from the medium-sized hyaline cells of the exudate. Why cannot some of the mononuclear cells of the exudate be hsematogenous ? There is, apparently, no reason why we should deny this hsematogenous origin of some at least of these cells, nor would it seem that, making this admission, we land ourselves in further difficulties. On the contrary, the evidence accumulating of late years appears to point in one direction, namely, that the mononuclear cells seen within the vessels during the process of inflammation are similarly of endothelial origin. Metchnikoff, from 1883 onwards, was the first to suggest that the large mononuclear leucocytes seen in vessels and lymph-glands are identical in their properties and characters with the endothelial cells of these tissues, and he directed attention to their peculiar properties of ingesting other leucocytes, and named them " Macrophages'' (a barbarous but a convenient term). EufFer's (57) studies of the lymph-glands wholly confirmed these observations. The fullest studies upon the histology of these cells are by Mallory (58), who described, with great detail, the large cells with slightly -staining, grooved, or indented nucleus, present more particularly in the lymph-glands in typhoid fever, and possessing, in short, all the characters of Metchnikoff's macrophages.- He describes them as Digitized by Microsoft® 76 INFLAMMATION pt. n originating from the proliferation of the endothelial cells of lymph -spaces, lymphatic vessels, and blood vessels. He has observed their mitosis, and has demon- strated the migration of such proliferated endothelial cells into the adjoining connective tissue (Fig. 6). These observations were confirmed by Councilman in his studies upon keratitis (29). We have, indeed, to recognise the very active part played by the vascular endothelium in inflammation, its pronounced proliferative and phagocytic properties. As pointed out by Abbott, Fia. 6. — Large cells of endothelial origin (macrophages of Metchnikoff) from centre of lymph-gland in typhoid fever which have actively taken up lymphocytes (i.) and red blood-corpuscles {r. h. c). — Mallory. Nicholson, and myself (59), within ten minutes after inoculating the B. coli into the circulation, the endothelial cells of the liver capillaries are swollen and have taken up numerous bacilli (Fig. 7). Before our observations, Werigo (60) had demonstrated the process whereby hepatic endothelial cells give off pseudopodia, by which anthrax bacilli are seized and subsequently englobed. Eecently Behring and Much (61) have called attention to the great phagocytic powers of the endocardial endothelium. As Beattie points out, in omental in- flammation the cells lining the veins become swollen Digitized by Microsoft® CH. X HISTOGENOUS LEUCOCYTES 77 and then detached from the wall, and various stages of the separation can be made out. Study of the sinuses of the spleen in typhoid (Mallory) shows the process very well ; the lining cells swell to three or four times their original size and become separated, so that a sinus may become distended with these free cells. As they swell, their cytoplasm becomes vacuolated, and poly- morphonuclears and other cells are seen to be ingested. Without entering into a discussion of the finer details of nuclear staining {vide Seattle's article) I would point out that the evidence now accumulating tends to the conclusion that Ehrlich's mononucleated non- granular ^n Fio. 7. — Endothelial cell of capillary of rabbit's liver, fifteen minute.s after intravenous inoculation of culture of B. coli, showing bacilli ingested and under- going disintegration. (The whole of the nucleus is not here in focus.) blood-cells (41) are of endothelial origin.^ Contrary, therefore, to Gulland, Saxer, and Uskow (62), I am of opinion that there is far from being a common origin for all the white blood-corpuscles ; one group at least is of endothelial origin, just as another is of lymphoblastic. And thus, recognising that the former are capable of migration, it must be admitted that cells of this order seen in exudates may be of both local and hcematogenous source. A word may here be said regarding the fate of these large mononuclear cells. Evidence seems to show that ' With these I do not include the neutrophilic and other myelocytes seen in the blood in certain disorders : they, it need scarcely be said, are cells of a different order, dearly derived from the bone-marrow. Digitized by Microsoft® 78 INFLAMMATION pt. n they do not, to any large extent, wander back into the blood-vessels. Various stages of degeneration of these cells may be recognised in the later stages of peritoneal inflammation ; they tend to be extensively vacuolated, and thus the conclusion is that they in the main eventu- ally disintegrate locally. While this appears to be true in connexion with bacterial inflammations, where more inert substances are taken up they clearly are capable of wandering in considerable numbers back into the circu- lation. Thus Metchnikoff points out that, if washed nucleated red corpuscles of the frog be injected into the peritoneum of a warm-blooded animal, large mononuclear cells containing the easily recognisable remains of the corpuscles can be detected after several days in the mesenteric glands, the vessels of the liver, and the spleen. Cells of the same order, which have not become free, evidently, according to Eanvier, take an active part in the formation of peritoneal adhesions. Muscatello, Graser, and Borst (63) unite in the opinion that the endothelium of serous surfaces can form connective tissue, though of late von Brunn (64) and Monckeberg have strongly contested this view, at least as regards serous endothelial cells. Their objections are not, to me, wholly convincing. More recently Baumgarten (65) has brought forward what appears to be definite evidence that vascular endothelium under mild grades of irritation gives rise to fibroblasts and connective tissue. Epithelial Leucocytes. — Mononuclear cells of endo- thelial origin seen in infiammation of solid tissues, noticeably in tubercle formation, are, from their general appearance, often spoken of as epithelioid cells. But if we employ the term epithelium, as is usual in English- speaking countries, to denote membranes derived from the primitive epiblast or hypoblast, this usage is apt to cause confusion. There are, however, true epithelioid Digitized by Microsoft® CH. X HISTOGENOUS LEUCOCYTES 79 cells ; I refer to the large phagocytic cells seen in pneumonic conditions, clearly derived from the flattened epithelium lining the air-sacs. With Pratt (66) we must recognise, in the pneumonic exudate, two forms of large mononuclear cells : (1) large cells, round or oval, with a crescentic, vesicular nucleus placed towards the periphery and apt to contain cell-inclusions, and (2) a cell present in the early stages of acute lobular pneumonia, larger than the polymorphonuclears, but not so large as the form just mentioned, but, like that, having a large, vesicular, indented nucleus and a very slightly granular protoplasm. These also are phagocytic, and Pratt expresses himself as doubtful regarding their origin. From his description, and since they are also found in the capillaries and in the tissues, it would seem clear that these are the endothelial mononuclear leucocytes men- tioned above, whereas the former are of epithelial origin. Free Cells — Leucocytes — derived from other Tissues. — - In the experimental inflammations of the cornea it can be recognised that the tissue-cells of the boundary zone in which there is no actual destruction undergo active proliferation. The corneal corpuscles, for example, as already indicated, become swollen, send out processes towards the point of injury, their nuclei stain more deeply, undergo division, and now two young cells of embryonic type are present where one had been before (vide Fig. 3, p. 30). These young cells are of the hyaline or mononuclear type, and, what is more, like the cells of endothelial origin, actively take up polymorpho- nuclear and other cells. Nor are the connective-tissue corpuscles alone in giving rise to cells of this order. Highly complex tissue - cells, like muscle fibres, when injured, are apt to exhibit direct division and multiplica- tion of their nuclei ; these nuclei are apt to separate from the main mass, carrying with them a small body Digitized by Microsoft® 80 INFLAMMATION pt. n of surrounding cytoplasm. This process in connexion with the degenerating tadpole's tail has been well described by Metchnikoff, Barfurth, Griffiths, and others (67). When so separated, these cells are not to be distinguished from hyaline mononuclear leucocytes and, like them, actively digest cell-debris, and so forth. Clasmatocytes. — In certain fine connective -tissue membranes, both in warm- and cold-blooded animals, there are to be seen considerable numbers of large, apparently wandering cells, elongated or much branched, with a rounded or elongated nucleus which Eanvier (68), on account of their tendency to cut off or leave behind them in their wanderings small remnants of protoplasm, has termed clasmatocytes. Marchand (69) has included them among his leucocytoid cells. Accord- ing to Eanvier, these originate as leucocytes — i.e. are derived from the blood — which have become more or less stationary in the tissues, and, on one hand, in their proliferation may give rise to cells of the exudate, and, on the other hand, may develop into true connective- tissue cells. While agreeing with Eanvier in this latter respect, Marchand denies that they originate from ordinary leucocytes, and regards them as identical with what Saxer (70) has termed "primitive wandering cells," which can give rise to leucocytes and nucleated red corpuscles. He thinks that by repeated division they develop lymphocytes, and that they gain entrance into the circulation as a form of mononuclear leucocyte, and, as already stated, that they may take part in the formation of connective tissue. Maximow concurs in holding that they may form fibroblasts and mononuclear " poly blasts." But now, as Lubarsch (71) points out, an identical form of cell is to be found in keratitis, with the same remarkable long processes, which are apt to be cut off and lie isolated in the tissues. If we then can Digitized by Microsoft® CH. X HISTOGENOUS LEUCOCYTES 81 determine the nature of these cells, we may arrive at some conclusion between these divergent views, but here, I must confess, there are difficulties. Lubarsch regards the characteristic corneal cells with spear-like processes as derived from mononuclear leucocytes which wander into the part. Grawitz (72), on the other hand, holds that these cells are modified corneal tissue -corpuscles. Councilman, and before him Senftleben, are very clear in their descriptions of the way in which, in certain grades of keratitis, the peripheral zone of corneal corpuscles Fig. 8. — Clasmatocytes. After (1) Ranvier and (2) Maximow. enlarge, send out processes into the necrosed area, and proliferate. This process we have just described. Their statements, thus, are in agreement with that of Grawitz. It will be seen, reading over the description of these various forms of cells which we regard as histogenous, as distinguished from haematogenous, that certain features are common to all of them : the tendency to attain to large size ; the amoeboid character ; the rounded, or, at most, kidney-shaped nucleus ; the tendency to take up other cells ; the liability, on the one hand, in prolifera- tion, to give off wandering cells of the mononuclear type, on the other hand, to develop into fixed tissue - cells. G Digitized by Microsoft® 82 INFLAMMATION pi. n Taking all these facts together, it will be seen that the clasmatocytes group themselves with the histogenous group of wandering cells, and as such I must classify them. In short, much, if not all, of the controversy regarding these different forms of cells becomes assuaged if we regard the cells of the mouonuclear type with rela- tively abundant protoplasm — the so-called hyaline cells ■ — as of endothelial and tissue origin, whether they occur within the blood or in the inflammatory focus. To those who have not followed the copious literature of the last few years these questions regarding the nature of the different forms of cells seen in inflamma- tion may appear to be small and unimportant, and the controversy regarding them to be very petty. But much depends upon the proper solution of this question, more particularly as regards the nature of the new -formed tissue which develops in areas of inflammation, and the difficulty in arriving at correct conclusions is very great. Any one who has studied inflammatory tissues will find out that, at first, classification of the different forms of cells seen seems to be almost hopeless. As a matter of fact, the youngest forms of newly developed cells are often so exactly alike that no means at present at our disposal serve to distinguish them; hence, for example, the controversy whether the large mononuclear cells give origin to lymphocytes. It is only by carefully following the successive stkges seen in the proliferation of any one form of cell that we can arrive at any conclusion, and then by a combination of methods, (or the employment of only one or two methods of staining is apt to mislead. Let me once more repeat that I am fully prepared to find that others do not agree witli the conclusions here reached ; nay, more, I would add that I am personally fully prepared to modify my views regarding these cells in the light of furtlier research. In the meantime, to sum Digitized by Microsoft® HISTOGENOUS LEUCOCYTES 83 up, let me say that the completed table of the leucocytes concerned in inflammation would appear to be the following ^ : — fPoLYMOKPHONTiOLE AK (polynuclear, finely granular oxyphil, neutro- phil, and amphophil cell). EosiNdPHiL (coarsely graimlar oxy- phil, macroxycyte). LYMrHOOYTE (? of two types). Plasma-Cell (? histogenous). Endothelioid Leuoooytb (mono- nuclear leucocyte, hyaline cell (in part), "epithelioid cell" (in part)). r Epithelial wandering cell (large hyaline cell, in part). J Connective Tissue wandering cell (including Clasmatooyte). Muscle and other tissue wander- ing cells. a Originating in adult mammals from the bone-marrow, and migrating from the blood into the inflammatory area. Originating fiom lymphoid tissue and from vascular and other endothelia re- spectively ; present in in- flamed area either by migra- tion from blood or as result of local proliferation. Originating locally as result of local tissue proliferation. In the previous edition the Mast-Cell was placed " very doubtfully " among the hsematogenous leucocytes. But whether seen in the blood or in the tissues in chronic inflammation this cell is degenerate in appearance, nor is there any evidence that it migrates from the blood into the tissues. Whether it is a degenerate plasma-cell or clasmatooyte, and so histo-hsematogenous or a degenerate histosenous cell is still undetermined. The genetic relationships I would suggest are indi- cated in the following table : — ^ It must be clearly borne in mind that all the forms encountered in the blood in various morbid states are not included in this table. A concise description of these other forms, with their ^jresumed relationship, is to be found in the article, by R. C. Cabot (73), in Osier and McGrac's System of Medicine. Digitized by Microsoft® 84 INFLAMMATION PT. II rt o w i-l ^ M o rt ;?H as w R » -< ^ b OT n P r> 03 O g t^ M O >^ ta P5 o H !^ <; S ^ g ^ .^ O y rx eS pj -=1 ^ 1^ U2 W S o :> rt H w ■>■, w H N O a 03 a O s T3 < O li o la "r. n 'pj !D o o o ^ ^ ^J 'S R '=^ K S i* '^ « p R a bO H 5 3 < 3 « la zn H tj H fi ?^ -A Digitized by Microsoft® CHAPTER XI SUMMARY OF PROPERTIES OF DIFFERENT FORMS OF LBUGOCYTES And here, though in so doing I to some extent anticipate and refer to matters to be discussed in some detail later, it is most convenient to sum up briefly the facts determined regarding the parts played by these various forms in inflammation. Polymorphonuclear Leucocyte. — In acute inflammation, when the irritant is not too intense, this is the form most often attracted to the focus of irritation, migrating most rapidly and in the greatest numhers. It is the characteristic pus cell ; is actively phagocytic, particularly for bacteria ; secretes bodies of the nature of enzymes notably, as shown by Leber, Fr. Miiller, and Jochmann and others, of a proteolytic nature, and, either while active or in the process of dissolution, liberates antitoxic and antibacterial substances. It may — ( 1 ) wander back into the lymphatics or blood-vessels ; (2) undergo dissolution and disintegration in situ ; or (3) be ingested by the proliferating tissue-cells and mononuclear leucocytes. It has nothing to do with tissue formation (74). Eosinophil Leucocyte. — This is also actively attracted, and that at an early period, towards the inflammatory focus, migrating from the surrounding tissues and also from the vessels, but it is never the preponderating cell present. In peritoneal inflammations it is found in great numbers in the omental vessels, and in sub-acute and chronic inflammations of certain tissues, such as the skin, may also be relatively abundant. Very rarely is it seen to ingest bacteria, so that, to all intents and purposes, it is non-phagocytic. Kanthack and Hardy (44) and Hardy and Wesbrook (75) have 86 Digitized by Microsoft® 86 INFLAMMATION pt. n ascribed a secretory activity to these cells, associated with the reduction in number and apparent discharge of the coarse granules, but later observers have failed to confirm their observations. The mode of action, therefore, of these cells remains unsettled. Opie has noted (76) that, during the course of various pyogenic in- fections, this form of cell disappears wholly or in part from the peripheral circulation, and after injection of a variety of bacteria into the peritoneal cavity of guinea-pigs he noted a similar disappearance ; but now, examining the mesentery, during the height of the infection, the eosinophils were found collected in the blood-vessels, actively migrating into the peritoneal cavity, where they were collected in considerable numbers upon the surface of the omentum. They clearly, therefore, have a part in the inflammatory process, but what that part is must still be considered undecided ; while there are indications that they proliferate in situ, all observers agree that they take no part in the formation of new tissue. Mast-cell. — This is seen particularly in sub-acute inflammations (the coarse basophil granules, staining intensely with oarbol-thionin and basic aniline dyes, and taking on a metachromatic nuance, must not be mistaken for clusters of small cocci). The nucleus stains feebly, according to the usual descriptions. Professor Miller of the University of Missouri has shown me his preparations, and permits me to refer to them. They definitely show that what has been taken for a feebly staining nucleus is a court or area where once the nucleus had been. The actual nucleus undergoes dis- integration and discharge. This cell is sluggishly amcEboid, and may detach portions of its cytoplasmic processes with their contained granules along the track taken by its pseudopodia. Nothing has been made out regarding the activities of this form of cell, save that Maximow shows that in the course of the inflammatory pro- cess it undergoes atrophy and disintegration (77, 78, 79). Professor Miller's studies confirm these views, and indicate further a complete want of relationship between the relative abundance of hsemal and tissue mast-cells in inflammatory states. Schridde indicates that this type of cell within the tissues is a rare variety of plasma-cell. Cabot calls attention to their frequent association with eosinophilia. Lymphocyte. — This is only slightly amoeboid, and does not migrate very actively from the vessels to the injured area in acute inflammations. It is, however, capable of this migration, and, in some chronic inflammations, is the preponderating cell ("small round cell"). It is found more particularly in masses around the vessels, and this as a result of — (1) migration ; (2) proliferation of the pre-existing lymphoid tissue. It is not phagocytic for bacteria, but may ingest particles of inert matter. According to Bergell (80) Digitized by Microsoft® cH. XI , SUMMAEY OF PEOPEETIES 87 lymphocytes obtained from a tuberculous focus possess a definite fat splitting enzyme or enzymes, which is still active at a heat sufficient to destroy the cells. The small lymphocyte, with a scarcely noticeable zone of cytoplasm, may give origin to the middle-sized lymphocyte, with more cytoplasm and deeper staining round or oval nucleus, and to the plasma-cell. There is no evidence that these plasma-cells are actively wandering, or that they return to the blood ; they occur especially in connexion with the formative and chronic inflammations, but whether they actively participate in the formation of new fibrous tissue is still a matter of debate. Histogenous Wandering Cells. — These appear in the inflammatory area in general at a definitely later period than do the polymorpho- nuclears and the eosinophils, and in certain forms of inflammation {e.g. of serous membranes) may become the preponderating type, exhibiting well-marked phagocytic properties, being not so active as regards most species of bacteria as are the polymorphonuclear leucocytes, but peculiarly active as regards other cells and cell- debris. They are sluggishly motile, and though those of vascular endothelial origin may migrate from the vessels into the tissues, they are rarely recognised passing back into the vascular system from the inflammatory area ; they are apt to become vacuolated. They multiply both by direct division and mitosis. They may — (1) undergo local necrosis and disintegration ; (2) may form giant- cells, either by plasmodial fusion or by direct division of the nuclei ; or (3) may be active factors in the formation of new tissue. Certain forms {e.g. those derived from corneal .corpuscles, and the clasmatocytes) give off frequently long pseudopodial processes. A word should here be said concerning sundry cells of later development, appearing as a result of inflammation — ^giant-cells, Eanvier's cells, and Gluge's corpuscles. Of these the last are evidently leucocytes of the hyaline type which have taken up the fatty products of tissue- degeneration ; the second — colossal cells breaking down with great ease — are of endothelial origin. Giant-cells would seem to be of more than one variety ; some appear to be due to aberrant cell-growth, wherein the nuclei undergo division . without the protoplasm of the cell- body following suit. The characteristic giant-cells of tuberculosis and chronic inflammation may now be said Digitized by Microsoft® 88 INFLAMMATION pt. n with fair certainty to be plasmodia, in all respects comparable to the masses of fused cells seen to form in the lower animals around foreign bodies, and by Kanthack and Hardy around masses of bacteria in the lymph of frogs outside the body. The observations of Borrel (81), Duenschmann (82), and Faber strongly support this opinion. Hektoen's careful studies tend also thereto (83). But while this is the case, it has to be admitted that in some giant cells of endothelial origin developing in the course of sub-acute inflammation direct division is to be seen affecting the nuclei, as demonstrated by Duval and White in their studies upon experimental glanders (84). There is indeed no reason to be adduced why both cell fusion and amitosis should not manifest them- selves in the course of development of an individual giant cell. Digitized by Microsoft® CHAPTER XII PHAGOCYTOSIS In the case of most pathogenic micro-organisms, after inoculation into the organism, a very considerable pro- portion are to be discovered, sooner or later, within wandering cells which have collected in the region of inoculation. I have already mentioned more than one case of this nature in discussing the comparative pathology of inflammation. Evidently under certain conditions one of the functions of certain of the leucocytes is to attack and incorporate bacteria. The leucocytes having these properties in mammals are more especially the polymorpho- nuclear and the non-granular or faintly granular mono- nuclear cells of endothelial and tissue origin ; the former, as already indicated, migrating from the blood, coming more rapidly into action and being most active from a very early period in tissues abundantly vascularised ; the latter, in the main of local development, becoming active at a later period, and then acting as phagocytes towards other cells as well as bacteria. It is, for instance, the polymorphonuclear cell which is found in overwhelming numbers in an extending subcutaneous abscess, and these are seen to contain great numbers of the micrococci. The conditions leading to this phagocytosis have been worked out in remarkable detail by Metchnikoff. He has amply demonstrated that the microbes can be taken Digitized by Microsoft® 90 INFLAMMATION PT. II up in a living condition. Thus, if the Vibrio Metchnikovi (a form closely allied to the cholera spirillum) be inoculated into the anterior chamber of the eye of an immunised animal, within a very few hours phagocytes are seen filled with the small, slightly curved vibrios. If now one such ceU be isolated, placed in a drop of broth upon a cover-slip, made into a hanging-drop preparation and examined under the microscope, it is -of <£■' Fig. 'J. — Kesolution of acute infectious disease (relapsing fever) si^Ieen pulp of monkey (a Macacus), showing (a) microphage, raultinuclear, with incepted spirochictes ; (^) solitary, and (c) forming dense tangle, (rf rf.) nuclei of splenic tissue (Zeiss, tVi ocular 4 ; X 1515 diam.). — Metcbnikoff. seen that the broth causes the death of the leucocyte ; while with time, and favourable temperature, the microbes proliferate rapidly and completely fill the corpuscle until it disintegrates, whereupon, they proceed to multiply in the surrounding fluid. This seizing and incorporation of microbes does not then necessarily lead to their death. In certain cases of acute disease there may be abundant phagocytosis, and the disease progress nevertheless ; the phagocytes being destroyed by the products of the incorporated organisms. This is the case in mouse septicemia, in swine erysipelas, and (as has been shown Digitized by Microsoft® CH. XII PHAGOCYTOSIS 91 by Gabritchewsky (85) iu diphtheria. As Eoux remarks : " lis ont fait de leur mieux en englobant les microbes, Fig. 10. — Two giant-cells, seen under liigh magnification ( x 1515 diam.), from a rodent, the spermopMle, inoculated witlx tuberculosis, to show stages in the destruction of the bacilli, a, Unaltered bacillus ; &, bacillus staining badly, and with greatly thiclcened capsule; c, bacillus granular and breaking up; d e, "shadows." — Metchnikoff. mais ceux-ci se sont adaptes au milieu int^rieiir des cellules, et ils ont triomph^s" (86). In other less acute diseases, such as gonorrhoea, and in chronic maladies, such as in tuberculosis, leprosy, and Digitized by Microsoft® 92 INFLAMMATION pt. ii glanders, the bacilli may ia certain stages be found within the cells and rarely free in the lymph-spaces, they appear to be almost parasitic, after the manner of the microsphajra previously referred to as infesting the amoeba. In these cases it would seem as though the toxic properties of the microbes and the antagonising powers of the cells were nearly balanced. In tuberculosis, for instance, it is not unusual to find in the giant-cells some bacilli which evidently are undergoing degenerative changes, staining poorly and irregularly, or but faintly traceable as unstained, translucent shadows, while else- where they are apparently proliferating despite their intracellular position.-' And this equality, or almost equality of the resisting powers of cells and microbes may explain the chronic nature of the diseases above mentioned. Nevertheless, in general, it may be stated that there is some relationship to be recognised between the amount of phagocytosis and the virulence of the microbe ; with a given hacterial species the more virulent the microbes, the less the proportion of them taken up by the cells, the longer the time before the phagocytes come into action, As in the unicellular organism, so in the wandering cells of Metazoa the mode of destruction of the included microbes can, under suitable conditions, be seen to be digestive. Several observers have seen the anthrax bacillus, in frogs and other animals, wholly or in part surrounded by a vacuole developed within the leucocyte ; and, as an evident result, the portion so surrounded has been seen ^ It is, however, unsafe to declare in all cases that because a micro- organism continues to stain well therefore it was living at the moment the preparation was taken and fixed by heat. Thus in pneumonia after the crisis a fair number of diplocooci may be found within the leucocytes of the expectorated contents of the alveoli, and these may stain perfectly well ; yet it may be impossible to gain a single growth of the diplococcus from the same material. Digitized by Microsoft® OH. XII PHAGOCYTOSIS 93 to become swollen and fainter when stained, until it has undergone a veritable digestion and dissolution. By the use of appropriate reagents the vacuoles in general are seen to be faintly acid in contrast to the more alkaline surrounding cytoplasm. As with the lower organisms, so with the wandering cells of the higher, there is an evident attraction, or chemiotaxis, whereby these cells pass towards the microbes and their products. The chemiotactic properties of the wandering cells have been especially studied by Fig. 11. — Phagocytes, macrophage and microphage, to show stages of digestion and destruction of bacilli, from spleen and eye respectively of white rat with anthrax. In 1, pai-t of the bacillus is unaffected, but a vacuole has formed around the other part, which further has now lost the power of tak ng the stain. In ^, various stages are seen, the bacilli passing through the granular, badly staining, to the vacuolated, unstained stage, until finally but faint '* shadows " are observable (Zeiss, ^ oc. 3). — Metohnikoff. Pekelharing (87), Leber (34), Massart and Bordet (88), and Gabritchewsky (85). Of the results obtained by these observers the . most important are that leucocytes are variously attracted towards various substances. Thus Leber found that the introduction into the system of finely-powdered copper and various compounds of mercury caused an abundant collection of the wandering cells around the particles, while powdered gold, silver, and iron exerted no such attraction. Gabritchewsky and Buchner (89) showed that the products of bacterial growth in general possessed chemiotactic properties yet more powerful than simple chemical compounds. While the Digitized by Microsoft® 94 INFLAMMATION pt. n degree of positive chemiotaxis is found to vary within wide limits, the examples brought forward of negative chemiotaxis exerted by bacterial products have so far been very few — so few as to support the contention of the late Prof Kanthack (90), that it is very doubtful whether any microbes by their products actually repel the leucocytes, though they are capable of causing the rapid destruction of the attracted leucocytes, and so of rendering the area around the microbes relatively free from wandering cells. This chemiotaxis would also seem in general to be in the inverse ratio of the virulence of the microbes. I say in general, for with chemiotaxis as with phagocytosis there appear to be exceptions to any uniform law ; and cases can be brought forward — of diphtheria, for example — in which the leucocytes, instead of being repelled, are attracted in great numbers to the region of inoculation of a most virulent bacillus. Indeed it may be doubted whether it is the bacterial toxins as such that, diffused into the surrounding medium, constitute the force attracting the leucocytes towards the bacteria. We now have come to distinguish two orders of pathogenic microbes, those which during active growth give off diffusible toxins, and those elaborating toxins which during active existence are not diffused, but remain intracellular (endotoxins) (91), so that the medium in which they grow has little or no toxic effects, although if the bacteria be collected and frozen at the lowest of temperatures and then crushed, their freed body-juices are found to be extraordinarily toxic. [MacFadyen and Rowland (92).] The diphtheria bacillus belongs to the first order, forms like the B. typhosus and the cholera spirillum to the second. It is only with the death of the bacteria of this latter order that the toxins are liberated to any extent. Now as regards chemiotaxis Digitized by Microsoft® OH. XII PHAGOCYTOSIS 95 and phagocytosis we can draw no line of demarcation between the two orders. Or, more accurately, up to the present there has been no adequate study of the inter- action between leucocytes and bacteria of the exotoxic and endotoxic groups respectively. It is suggestive that the " type " producer of exotoxins, the diphtheria bacillus, induces active chemiotaxis and phagocytosis, followed by disintegration of the leucocytes, while the tubercle bacillus which characteristically gives rise to endotoxins is weakly chemiotactic, gives rise to a leisurely phago- cytosis, and persists for long within the leucocytes witli- out setting up pronounced reaction. The law would seem to be not that the extent of positive chemiotaxis is in inverse ratio to" the virulence of the different species of bacteria as towards the human being or other larger animal, but that with a given species of microbe the greater the virulence of the strain the less the positive chemiotaxis. It has still to be determined whether it is the toxin as such, or some other diffusible substance produced coincid- ently, that attracts the leucocytes towards the bacteria. A very good study of the action of bacteria of different degrees of virulence can be made by repeating an experi- ment of Metchnikoff. The rabbit is an animal susceptible to the growth within its tissues of the bacillus of anthrax. As is well known, there are various means whereby the virulence of this microbe can be diminished ; so that if cultures of the '' attenuated " bacillus be inoculated into susceptible animals, these, instead of causing a fatal disease, induce but a transient local inflammatory disturbance, accompanied by fever, and followed by complete recovery. If now a small quantity of a virulent culture of the bacillus be inoculated into the one ear of a rabbit, and an equal quantity of an attenuated culture into the other, the results are very instructive. Within twenty-four hours it can be noticed that an acute Digitized by Microsoft® 96 INFLAMMATION pt. n inflammation has been induced in both ears ; in both the vessels round the seat of inoculation are greatly con- gested, but whereas at the seat of inoculation of the virulent organism there is a serous inflammation so intense that the skin is raised and separated from the subjacent tissues by a clear, transparent, reddish fluid which also infiltrates the deeper tissues, in the other ear there is not nearly the same amount of swelling and serous exudation ; the region of inoculation is morei opaque and solid. Upon more minute examination the serous fluid in the first ear is found to contain relatively very few leucocytes ; the firmer mass in the second is composed of a huge aggregation of leucocytes. Before proceeding farther it will be well to sum up the phagocytic hypothesis of inflammation as upheld by Metchnikoff and those who see in this phenomenon the all-important factor in inflammation and the repair of injury (as also in the production of immunity), in order that, having put clearly forward the tenets of those upholding the hypothesis, I may the more readily state wherein lies the strength and wherein the weakness of the doctrine. This hypothesis may be summed up in the following theses : — 1. That certain of the leucocytes present in the blood and lymph, notably the polymorphonuclears (microphages) and the large mononuclear hyaline cells (macrophages), are capable under certain conditions of taking up bacteria which have gained entry into the system. 2. That in addition to these, the splenic corpuscles, the cells forming the endothelium of capillaries, and other fixed cells of mesoblastic origin, possess the same property, although tbey exert it to a less extent. 3. That these phagocytes seize upon and destroy living and active microbes under certain conditions. Digitized by Microsoft® OH. XII PHAGOCYTOSIS 97 4. That the more virulent the microbe the less the ^ tendency for the leucocytes above mentioned, and for the other fixed cells, to take up the bacteria. The less virulent the microbe the more extensive the phagocytosis. 5. That in addition to this power on the part of certain cells (the phagocytes) to take up and destroy certain bacteria, another factor has to be called in to explain why the wandering cells of the body migrate towards the focus or foci where the micro-organisms have gained an entry into the body. This factor is the " ehemiotaxis " exerted by the products of bacterial growth, and by some other substances, such, for example, as the products of death of tissue and of wandering cells, and experimentally also certain chemical irritants as, for example, turpentine and mercury. In the case of the virulent microbes the leucocytes are not attracted to the focus of infection. There is a " negative " ehemiotaxis, and thus, in the absence of phagocytosis, the proliferation of the microbes takes place without hindrance ; whereas the less virulent microbes and their products attract the leucocytes, they exert a positive ehemiotaxis, so that there is a migration of leucocytes through the capillary and venous walls to the focus of . infection, and the leucocytes taking up the microbes tend to arrest the infective process. 6.. That the leucocytes may become accustomed and eventually attracted to substances from which at first they were repelled, and thus a negative may be transformed into a positive ehemiotaxis. 7. That the cells, having once acquired positive cheiniotactic properties in relation to the products of any specific microbe, retain and transmit these properties through a series of cell-generations, the length of which varies according to the microbe, the extent of the primary reaction, and the idiosyncrasies of the individual. H Digitized by Microsoft® 98 INFLAMMATION pt. n 8. That, consequently, the cure of zymotic or mycotic disease, whether localised or general, and immunity also, are mainly brought about by the activity of special cells (the phagocytes), and are primarily dependent upon the attraction existing between these cells and the products of bacterial metabolism. 9. The process of inflammation is essentially the endeavour on the part of the organism to promote the migration of leucocytes, and to aid the inclusion and destruction of the irritant. " The essential and primordial element of a typical inflammation is a reaction of phagocytes against the irritant [agent nuisible)." Or, more fully, " inflammation is to be regarded, on the whole, as a phagocytic reaction of the organism against irritants, — a reaction which at times is accomplished by the wandering cells alone, at times with the aid of the vascular (fixed) phagocytes, or with that of the nervous system." These are the main headings, if we may so term them, of Metchnikoff's hypothesis (for, to my knowledge, he has never formulated it clause by clause). Yet other data must be added to make it complete, data drawn from Metchnikoff's more recent studies (93), which we shall discuss in fuller detail later : — 10. The destruction of microbic irritants by the cells is a process of digestion: the cells elaborate ferments (cytases) which differ in their properties ; that elaborated by the microphages (polymorphonuclears) is termed by him microcytase ; that by the macrophages (hyaline mononuclears), macrocytase. These ferments are the main factor in the destruction of bacteria. 11. These ferments are formed and act within the living, active cell; they are endo-enzymes. But with the death and disintegration of the phagocytes (phagolysis) they become liberated, and, through their liberation, the body-fluids become bactericidal. Since cells which are Digitized by Microsoft® CH. xn PHAGOCYTOSIS 99 capable of acting as phagocytes liberate these cytases, the process is to be included as phagocytic. 12. It must be granted that when extracellular the cytases alone are incapable of causing bacteriolysis ; bacterial destruction is brought about by the interaction of the cytase and another product of cellular activity — the " fixateur " (immune body or intermediary body). While the cytases are not specific, acting indifferently on various microbes, the fixateurs are specific, a different fixateur being developed in the process of immunisation against each specific microbe. These fixateurs are actively secreted from the living cell, and are present in the humours and exudates of the immunised animal. Metchnikoff has relatively little to say -regarding these, but admits their existence, and further believes that they are developed from the same order of cells as are the cytases ; hence he holds that they also are to be con- sidered as results of phagocytic activity. I have laid down these later theses somewhat in advance in order to present the doctrine as a whole, and that I may the more easily take up the objections that have been raised, some of which have been well met by Metchnikoff and his fellow-workers, though others still, in my opinion, have not been fully controverted. In the terms of this hypothesis, then, phagocytosis is the all-important factor in the inflammatory process, the vascular, exudative, nervous, and other phenomena being auxiliary means whereby the phagocytic properties of the wandering and fixed mesodermal cells may be brought more fully into action : the determination of leucocytes that I have described is almost entirely to be attributed to an endeavour on the part of these cells to take up and destroy the irritant. To what extent is this doctrine to be accepted ? It must in the first place be laid down without the Digitized by Microsoft® 100 INFLAMMATION pt. n slightest hesitation that phagocytosis is a factor in inflam- matory processes ; no antagonist of the doctrine nowadays is prepared to deny this. Nay, more, each succeeding year we recognise more fully that it is an important factor. There is not a single bacterial disease that affects man in which, to my knowledge, it has not been shown that the causative microbes are liable to be taken up by the cells, if not in man himself, at least in other warm- blooded animals. And, by repeating a very simple experiment devised by Leishman (94), this phagocytic activity of the human white blood corpuscles can very easily be demonstrated. It is only necessary to clean the finger, take a drop of blood, mix it with an equal quantity of a suspension of any pathogenic organism, drop the mixture on a slide, place over it a cover-slip, place the preparation in an incubator at blood-heat for a quarter of an hour, then rapidly removing the cover-slip, fix the film and stain it by any good bacillary stain. Ordinary polymorphonuclear leucocytes present in the film can then be seen to have taken up, in this short time and under these not wholly favourable conditions, abundant bacteria. There may be twenty or more present in a single cell. The Resistance Period. — It is when a hypothesis has been applied with the object of attaining practical ends, and is found to afford the results expected, that its value is proved, and we would point out that one of the most important recent advances in abdominal surgery has been developed from a basis of this hypothesis of phagocytosis. As already indicated, the injection of various microbic and chemical irritants into the abdominal cavity is followed by a pronounced leucocytosis, follow- ing upon which, when particulate bodies are present, there is seen to be abundant ingestion by the cells. Taking these facts into consideration, Issaeff (95) Digitized by Microsoft® OH. XII PHAGOCYTOSIS 101 determined that, if a peritoneal leucocytosis be induced by intra-abdominal injection of saline solutions, serums, etc., and then (twenty-four hours later) various species of spirilla be inoculated also into the abdominal cavity, the resisting power of the animal to these pathogenetic microbes is very greatly augmented. Dr. Durham (46) confirmed and showed that this was true, not only of the spirilla, but of the B. typhosus and other microbes. He found that the leucocytosis — and the increased resistance — lasted for some four or five days. Von Mikulicz and other surgeons have made use of this " Issaeff resistance period." A day prior to performing any serious opera- tion, they inject nucleins, saline solutions, or serum, harmless in themselves, but capable of setting up an abundant leucocytosis. They have found that, thereby, they materially diminish the dangers of subsec[uent infec- tion ; the leucocytes, already in the peritoneal cavity in great numbers, take up and destroy bacteria which have chanced to gain entrance, before they have time to multiply. One has but to read Metchnikoff's fascinating work on L'ImmuniU dans les maladies infedieuses (93), to be impressed with the extraordinary diversity and number of the researches in connexion with various pathogenic organisms whereby the phenomena of phagocytosis have been established and confirmed. Yet, already in the course of discussion, there are one or two respects in which we are not wholly in agreement with the general terms in which the hypothesis is set forth. (1) We doubt, for instance, the actual negative chemiotaxis — the actual repulsion from bacterial irritants. At most, with Prof. Kanthack, we are prepared to see an absence of positive attraction. This, however, is a minor point and does not seriously affect the main question. (2) We have difficulty also in recognising that the extent of Digitized by Microsoft® 102 INFLAMMATION w. ii chemio taxis— and of phagocytosis — is in absolute inverse ratio to the virulence of the microbes. This obtains, we admit, in connexion with any one species ; the more virulent the members of that species, the less the phago- cytosis. But, comparing different species, it does not fully hold and, if virulence be dependent on toxic properties, then, when many of the most virulent bacteria do not diffuse out their toxins, we have to suppose that it is not the toxins but some other and diffusible sub- stance, elaborated pari passu with the toxins, which is the cause of the attraction. Here again, while disagree- ing, we do not think that this renders the hypothesis in its essence untenable. Granting this, phagocytosis might still be the all-important factor. (3) What deserves emphasis is that, by dwelling upon one function of the cells — that of phagocytosis — the hypothesis is incomplete. It is not permissible, in 'the first place, to expand the term phagocyte so as to include cells which do not eat, and if we agree that bacteria are destroyed and their toxins neutralised, not alone by intracellular but also by extracellular activities, substances being discharged into the lymph and blood plasma which arrest bacterial growth, neutralise the toxins, or lead to dissolution of the bacteria, then our hypothesis passes from being one of phagocytosis pure and simple into a " cellulo- humoral" one. Now we have to admit this, and, for a fuller comprehension of inflammation, have to appreciate duly all the factors that go to make up the very complicated picture. While we wholly agree with Metchnikoff that the later development of his hypothesis is a natural expansion, and while we understand the natural inclination to speak of it still as the phagocytic hypothesis, we find that the position is not clearly under- stood by every one, and the objection not infrequently raised that much that is now included in the hypothesis Digitized by Microsoft® OH. XII PHAGOCYTOSIS 103 is not phagocytosis at all, is difficult to controvert in a few words. It may further be urged with some justice that the extracellular and excretory activities of the body cells are minimised, and certain other factors in the process largely neglected. This notwithstanding, Metchnikoff's views have been purposely given this prominence. It is through him and through them, and through the active controversy and critical research initiated by these remarkable studies, that we have reached our present standpoint regarding, not merely inflammation, but the wider sub- jects of infection and immunity. And what is more, they are in our opinion in the main incontrovertible. Now, in order to arrive at what we personally regard as a wider and sounder view, it may be well to detail briefly and to criticise the more important of these researches directed against Metchnikoff's hypothesis. Digitized by Microsoft® CHAPTEE XIII THE HUMORAL HYPOTHESIS The first strong attack — and that when Metchnikoff upheld an uncompromising phagocytosis and nothing else — was originated by Nuttall (96). So long ago as 1874, Traube and Gschleiden (97) had called attention to the antiseptic properties of the blood, and in his presidential address at the London meeting of the Inter- national Medical Congress in 1881 Lord Lister had noted that a drop of putrid blood, teeming with microbes, if diluted with a little water, when added to pure blood that had been received into a sterile vessel, might leave that blood unchanged for days, the blood remaining sweet, and having, evidently, the properties of arresting the growth of the organisms of putrefaction. In 1887 von Fodor (98) of Buda-Pesth more definitely called attention to these bactericidal properties, but it was ISTuttall, then a Johns Hopkins student working under riiigge, whose exact studies called particular attention to the properties of the humours of the organism. In an attempt to repeat Metchuikoff's researches upon the destruction of the anthrax bacillus, this observer noticed that if he placed a fine canula containing a fresh culture of attenuated anthrax bacilli in the tissue of a rabbit's ear, there resulted in sixteen hours a rich cellular exudation ; but phagocytosis appeared not to reach its 104 Digitized by Microsoft® CH. xni THE HUMOEAL HYPOTHESIS 105 maximum for twenty-two hours, and even then half of the bacilli lay free and not taken up by the cells ; and he found, further, that the free bacilli showed involution and degeneration to the same extent as did the ingested. This led him to study the effect of blood-serum, defibrin- ated blood, and lymph upon the bacilli, and he discovered that these fluids had a remarkably rapid action, destroy- ing great numbers within a very few hours. Nuttall's very full research appeared to show conclusively that the bacteria -destroying power resided largely in the serum, and that in inflammation the exuded fluid rather than the leucocytes brought about the destruction of the microbes. Further, ISTuttall found that the bactericidal substance was destroyed by being subjected for one hour to a temperature of 55° C, so that blood-serum outside the body, thus heated, lost all its powers of arresting bacterial growth. A definite, if variable, quantity of bactericidal matter was present in a given quantity of the heated serum, capable of destroying a certain number of bacteria, so that, if more than that number were added, the excess survived and, in the course of a few hours, showed active multiplication. These observations were confirmed and extended by Nissen (99), Behring (100), and Buchner (102), and a most valuable series of contributions have been made by Haiikin (101), Buchner, Vaughan(103),Tizzoniand Cattani (104),Behring,Ehrlich and his pupils (105), and others, upon the nature and properties of the substances to be derived from the blood -serum of animals either naturally immune to certain diseases, or rendered immune by one or other procedure. What is more, it- has been recognised that two orders of substances are recognisable ; one capable of destroyiug pathogenic microbes, the other not de- stroying them, but rendering their products inert. We cannot here give these important observations in Digitized by Microsoft® 106 INFLAMMATION pt. n detail (93), as they bear more particularly upon the subject of immunity. It was shown from several sides that, in the blood-serum and removed body-fluids as also under certain conditions within the tissues, there occurs active destruction of bacteria without the bacteria being ingested by the cells. The experiments were so clear, so easy to repeat and confirm, that we can well remember the time when, to believe in phagocytosis, even as an auxiliary process in the arrest and cure of disease, was to be regarded as to be lacking somewhat in common sense. The destruction of bacteria in the economy was held to be almost entirely — in some cases entirely — - brought about by the action of the humours of the body. But this humoral hypothesis pure and simple was soon seen to be inadequate. Its upholders could not say how and whence the bactericidal substance was derived, and the more sera were studied — whether gained from healthy animals, from individual cases of the disease, from animals naturally immune to certain diseases, or those rendered immune by inoculation of this or that microbe — the more impossible it became to recognise any sure relationship between the bactericidal power of the serum and the extent of resistance displayed by the individual affording that serum. It was noted also that the different humours of the body differed in bactericidal properties in a way that could not be adequately explained in the terms of this hypothesis. Digitized by Microsoft® CHAPTER XIV THE CELLULO-HUMOEAL HYPOTHESIS If the serum and if the blood-plasma contain bactericidal substances, these must in all likelihood be developed by certain cells, and thus at bottom the humoral conception must be cellular ; and the very fact of the great increase in the bactericidal properties of the blood immediately on its withdrawal from the body, must suggest that in the changes which occur in the extravascular blood there is a liberation and solution of bactericidal substances. Now the first and foremost of these changes is the breaking down of the leucocytes as the blood begins to clot. It may, therefore, be that this breaking down of the leucocytes, with liberation of their contents, is capable of explaining the increased bactericidal action of defibrin- ated blood and blood-serum. This, let me repeat, is not phagocytosis, at most it is a function of cells which can act as phagocytes. If correct, it seems that that group of wandering cells which more particularly exhibit phagocytic properties is also able to bring about the destruction of bacteria and the neutralisation of toxins by other means. As a matter of fact evidence has steadily accumulated showing that more particularly the wandering cells of the body and also, probably, certain orders of fixed cells possess these other means. Many years ago Eibbert (107), in his studies upon ^ the fate qf 107 \ : ^ , ■ ''■ ^ I ' Digitized by Microsoft® ' \ \ '• '^ 108 INFLAMMATION pt. u spores of sundry species of mould (aspergillus and mucor) inoculated into the anterior chamber of the rabbit's eye, had found that two stages of reaction were to be made out ; at first the spores and developing hyphal filaments became surrounded by dense clusters of leucocytes which remained in apposition to but did not ingest the micro- organisms. They appeared to bring about a weakening and lowering of vitality on the part of the spores and filaments, so that, after a time, other cells wandering into the part could manifest their phagocytic action and take them up. Eibbert, it is true, attributed the lower- iug of vitality to the walling-in (" Wallbildung ") of the leucocytes and consequent lack of nutrition. The fact I'emains that he demonstrated a preparatory extracellular action upon the micro-organisms by the leucocytes. That the leucocytes contain bactericidal substances was first demonstrated by Hankin (101), who obtained from the lymphatic glands and spleens of animals immune to anthrax (dogs and cats), a proteid of the nature of a globulin, identical with Halliburton's cell- globulin /3, and having a bacteria-killing power similar to that possessed by blood-serum. In later observations upon the rat he showed that there was a relationship between the amount and activity of these " defensive proteids " and the power of resistance of the animal to the disease. Thus Hankin showed that in animals possessing the power of destroying bacilli, the organs containing the largest collections of leucocytes yielded notable quantities of a bacteria -destroying substance. These defensive proteids are now more commonly known as alexins, this name having been given to them by Buchner, who, beginning as a strong supporter of the humoral hypothesis, ended in assuming a position which more nearly approached that of Metchnikoff. It was shown by Denys and Havet (108), of Lou vain, that Digitized by Microsoft® OH. XIV CELLULO-HUMOEAL HYPOTHESIS 109 exudates rich iu leucocytes have a more intense bacteri- cidal power than has the blood -serum of the same animals, and that the blood and exudations of the dog freed from leucocytes, either by infiltration or by centri- fugal action, lose their bactericidal power, regaining it when the leucocytes are re-introduced. Buchner (109) fully confirmed these observations. He showed that, if sterilised emulsions of the gluten of wheat be injected into the pleural cavity of a dog or rabbit, its presence leads to the pouring out of an aseptic exudation peculiarly rich in leucocytes, and this exudation is much more bactericidal than is the blood or the serum of the animal. He noted further that, like the alexins of blood-serum, this bactericidal substance of inflammatory exudates is destroyed by heating to 55° C. Several other observers —Bail (110), Schattenfroh (HI), Van der Velde (112), Jacob (113), Lowit (114), and Bordet (115) — have obtained similar results, employing various methods. Thus it is now generally accepted that the alexins or bacteri- cidal substances of the serum, as of exudates, are derived very largely from the leucocytes, and that when, therefore, bacteria undergo destruction in the humours of the body without the intervention of cells, that destruction is indirectly due to the leucocytes. Yet another line of work independently points in the same direction. Vaughan (103) separated from blood - serum nuclein, a body which so far had been found exclusively in connexion with the nuclei of cells. His work was independently confirmed and extended by Kossel, working with nucleic acid, the main constituent of nuclein. This nuclein is either itself bactericidal or has a bactericidal substance in association with it. The presence of such a body in the serum is best explained by the disintegration of nucleated cells, i.e. of leucocytes. Clearly then leucocytes of certain orders contain Digitized by Microsoft® no INFLAMMATION px. n bactericidal substances ; can we recognise not merely a liberation of anti-bacterial substances by disintegrating leucocytes, but a functional active secretion of the same such as has been held by Kanthack and Hardy, and by Buchner and his school ? Metchnikoff largely denies this ; the rnicrocytase and the macrocytase, the digestive ferments of the two main orders of leucocytes, are, according to him, endo-enzymes, acting with the cell-body and only discharged with the dissolution of the cell. At a very early period it was shown by Nuttall that the blood-serum removed from the body acts far more rapidly and energetically than does the blood-plasma and lymph within the body. The disparity of action between the two is remarkable. Thus Lubarsch (116) has shown that in order to kill a rabbit by intravenous inoculation of anthrax bacilli into tlie circulating blood, at least 16,000 virulent bacilli must be introduced. In other words, the whole circulating blood is able to destroy only some 16,000 bacilli at a time. On the other hand, a single cubic centimetre of the blood-serum derived from such a rabbit can, outside the body, kill an even greater number of bacilli in a few minutes. The normal blood- plasma, therefore, does not appear to be actively bacteri- cidal, and this is confirmed by certain striking observations by Gengou (117). If rabbits' blood be obtained with every precaution against admixture with the body-fluids, be received into paraffined test-tubes, and be centrifugalised immediately so as to remove all the cells, a serum or plasma is obtained which will remain liquid for several days. So obtained, there has been a minimal breaking down of the leucocytes. This plasma has practically no bactericidal properties, but, on the contrary, serum from the same animal, obtained from blood allowed to clot, is actively bactericidal. In this process of clotting there is, as we know, an extensive destruction of leucocytes. Digitized by Microsoft® CH. XIV CELLULO-HUMOEAL HYPOTHESIS 111 But Gengou's experiments merely demonstrate that in the normal animal not subjected to bacterial invasion the leucocytes circulating in the blood do not actively dis- charge bacteriolytic substances into the plasma : they do not controvert the possibility that, under bacterial stimulus, the cells of the body actively secrete these bacterial substances. It is, we confess, difficult either to prove or disprove that this is the case. If bacteria or their pro- ducts be injected into the body-fluids, and these are found to become increasingly bacteriolytic, it may well be urged that the result is wholly due to resulting disintegration of the leucobytes. It must be noted further that other observers repeating Gengou's work (though often not his identical methods) have not gained such clear results (118). Pfeififer's Phenomenon. — A few years ago proof posi- tive of such exudation, not by leucocytes, it is true, but by endothelial cells, seemed to have been discovered by Pfeiffer of Berlin (119). If a few drops of a pure culture of the cholera spirillum be injected into the peritoneal cavity of a guinea-pig, vaccinated against cholera, and, a few minutes later some of the peritoneal fluid be ex- amined, it is seen that very few leucocytes are present, and, this notwithstanding, the spirilla, instead of having their usual curved "comma "-like form, have become globular, the majority staining badly and being dead. Outside the body the blood-serum of a highly immune guinea-pig has similar properties. If heated to 55° C. for an hour these properties are lost. There is, therefore, present in the peritoneal fluid, as in the blood-serum, a body of the nature of an alexin which clearly is, to some extent, responsible for this remarkable alteration in the spirilla. It is impossible to deal in detail with the important controversy that has raged regarding the meaning of Digitized by Microsoft® 112 INFLAMMATION this Pfeiffer's phenomenon. Suffice it to say that Pfeiffer regarded the substance causing the phenomenon as an excretion from the peritoneal endothelium; that Metch- nikoff demonstrated that it was best explained by what 1. 3. 'I , Jf- Fig. 12.— P/ei/er's Phenomenon. — Effect of liuman blood-serum upon spirillum cholerEe (1, 2) and bacillus typhosus (3, 4) respectively. In the two upper ligures the blood-serum has been heated to destroy the intermediate bodies (immune bodies, opsonins). Leucocytes have been added, together with a suspension of the bacteria, and the mixture placed at 37° C. for fifteen minutes. It is seen that the polymorphonuclear leucocytes take up the unaltered bacteria. In the two lower figures are shown the effects of the unhealed blood-serum. In other respects itlie treatment is the same. Under the action of the serum the bacteria swell up and become spherical, losing their jjower of taking the stain. There is equally active phagocytosis. In the leucocytes are to be seen some un- altered bacteria. These have been ingested before the serum has acted upon them. —After Wright and Douglas. he has termed ''phagolysis " — by the rapid clumping of the leucocytes of the peritoneal cavity upon the omentum, followed by their dissolution and liberation of bactericidal substances ; he has shown further that the phenomenon does not develop in connexion with body-fluids, such as Digitized by Microsoft® CH. XIV CELLULO-HUMORAL HYPOTHESIS 113 the aqueous humour, containing few or no leucocytes ; and that it does not occur if phagolysis be prevented ; while Bordet (120) demonstrated that the reaction needed the presence of two substances — an alexin or microcytase derived from the broken - down leucocytes, which is destroyed by heating to 55° C, and a second substance, not present in normal animals but present in the serum and peritoneal fluid of vaccinated animals, which is only destroyed at a temperature of 68 to 70° C. This substance belongs to the group of bodies which have been termed fixateurs, amboceptors, immune bodies, intermediary bodies, etc. In short, says Metchnikoff, it is the breaking down of the peritoneal leucocytes that is the main factor in bringing about Pfeiffer's phenomenon. But where does the second substance, the intermediary body, which also is essential for the development of Pfeiffer's phenomena, come from ? It is present, not only locally, but in most of the body humours. To be brief, there is no evidence that this substance is, under normal conditions, purely intracellular. The evidence, so far as it goes, is all to the contrary. As with the allied group of substances known as the agglutinins and the whole group of immune bodies produced in the development of immunity, these fixateurs or intermediary bodies are widely distributed in the organism, even in the excreta of immunised animals. They appear to be actively produced, and that over relatively long periods, and so we must conclude that they are products of living cells. This, at least, is the view accepted by all who have studied them, and, though he has singularly little to say regarding them, Metchnikoff's view partakes of this opinion {vide 93, p. 816). He regards them as also, in the main, produced by those cells which, under other conditions, act as phagocytes. That is, to say the least, I Digitized by Microsoft® 114 INFLAMMATION rx. n doubtful. As Sir A. E. Wright (121) points out, the organisms which exhibit Pfeiffer's phenomenon under favourable conditions — notably the spirillum of cholera and the B. typhosus — may be taken up by the peritoneal leucocytes very rapidly, before the phenomenon has manifested itself When so taken up, they do not swell up and become globular, though others, ingested later, have a globular appearance. If the phagocytes themselves produce the intermediary substance, why should not the bacteria undergo like alteration ivithin the bodies of the phagocytes ? It is only outside these cells that the change takes place. Wright's Phenomenon. — Where, indeed, these inter- mediary bodies are produced is, at the present time, an open question. That they play an important part is most evident, but, what is more, the recent observations of Wright and Douglas and other co-workers (121) show- that, in connexion with the majority of pathogenic bacteria, phagocytosis occurs with difficulty, if at all, in the absence from the body-fluids of certain of these inter- mediary bodies. These particular ones they have termed opsonins} Wright and his fellow-workers confirmed the observation of Nuttall, Stern, and others that blood-serum has no bactericidal effect upon the pyococcus aureus. They were thus led to investigate to what extent active phagocytosis might explain the destruction of pyococci gaining entrance into the organism, and found that an active phagocytosis occurred, but only under certain conditions. If, along the lines of Leishman's experiment, the corpuscles are, by centrifugalisation, separated from the blood, and now a mixture be made of the washed white blood corpuscles, the serum, and a suspension of the pyococci, and this mixture be kept for a quarter of an hour at the temperature of the blood, active phago- ^ From opsone (or ohsono), " I cater for." Digitized by Microsoft® OH. XIV CELLULO-HUMOEAL HYPOTHESIS 115 cytosis occurs ; the polymorphonuclear leucocytes are seen to contain, each of them, numerous cocci. But if now, before making this mixture, the serum be heated to 65° C. and then added, there is little or no phagocytosis. This points to the existence of something in the unheated serum which favours the process of ingestion of the bacteria, and, as a matter of fact, they show that a component of the active serum has a preparatory action upon the suspended bacteria, so that the bacteria subjected to an unheated serum for a time and then placed in the heated inactivated serum are taken up more readily than those placed direct into an inactivated serum. They show, further, that in the process of rendering an indi- vidual more refractory to pyococcic infection, his serum comes to contain increasing quantities of this opsonin or intermediary substance. So that, taking the washed white blood corpuscles of an ordinary individual, adding these to a mixture of the serum of the immunised indivi- dual with a suspension of pyococci, the leucocytes of this normal individual take up a much greater number of the cocci in a given time than do washed white blood corpuscles of the iHim-MTOsef? individual suspended in thecentrifugalised serum of the normal individual, to which a culture of pyococci has been added. What is true of the staphy- lococci obtains also with the long series of other, bacteria, the only exception noted being in connexion with members of the diphtheria group. These opsonins are found to be distinct from alexins or bactericidal sub- stances, apparently distinct also from the ordinary inter- mediary bodies, for their activity is greatly lowered by subjection to a temperature of 55° C. But, as with the intermediary bodies, it seems improbable that they are secreted by the phagocytic cells. Sir A. E. Wright and Douglas found that the blood-serum of cases with abscesses might be from six to ten times more active in promoting Digitized by Microsoft® 116 INFLAMMATION pt. ii phagocytosis than the serum extracted from the pus of the abscesses. Are they secreted by the phagocytic cells or by leucocytes of any order ? It would not seem possible to give a definite answer to the question at the present time. Wright and Eeid (122) pointed out that the exudates produced by a given bacterium may contain no opsonins of any order, an observation which has been confirmed by Opie (123). If leucocytes secreted these substances, then we should expect that with collection of leucocytes, the containing fluid should on the contrary afford opsonins in the greatest abundance. Aggressins. — But here other considerations have to be taken into account, which would seem adequate to explain the absence of opsonins in these circumstances. As pointed out some years ago by Ainley Walker (124), as again by Welch (125), if the cells of the organism produce antibodies of various orders when stimulated by microbes and their products, it is at least probable that the resistance of these microbes to the action of the body humours is to be explained by a reciprocal production of antibodies by them. And, as a matter of fact. Bail (126) has demonstrated the existence of bodies of this nature. Injecting typhoid bacilli, for example, into the pleural cavity of animals of the laboratory and so setting up a serous inflammation, he collected some of the fluid, centrifugalised, to remove the bacteria and cells and gained a fluid that was apparently inert, — that could be inoculated into other animals without causing any symptoms. But now if he inoculated this fluid into those animals along with a sublethal dose of the typhoid bacilli, that dose forthwith became lethal. 'Instead of the bacteria being destroyed, they underwent active proliferation. Clearly there is a something in the inoculated exudate that has paralysed the protective Digitized by Microsoft® CH. XIV CELLULO-HUMOEAL HYPOTHESIS 11 7 agencies of the body, something presumably supplied by the bacteria which had grown in the fluid, and this something is not of the nature of a toxin, for the fluid is not toxic. To this Bail has given the name of aggressin. Hence where an exudate is found devoid of opsonins, it is permissible to surmise either that the aggressin s given off by the bacteria have neutralised the opsonins present in that exudate, or that the leucocytes of that exudate which under normal conditions should have afforded opsonins have been paralysed by the aggressins, and opsonin production has been inhibited. Fig. 13. — Granular (oxyphil) leucocytes attacking and coming into apposition to ciiain of B. raTtiosus. From a Ziegler's chamber preparation, peritoneum of guinea-pig. — Kanthack and Hardy. These researches of Sir A. E. Wright have established beyond doubt that besides the actual engulfing and digestion of bacteria by the leucocytes another factor has to be taken into account (127). It is interesting to note that the late Prof Kanthack and Mr. Hardy (44), whose observations I quoted in a previous edition of this article as affording direct evidence that the leucocytes secreted bactericidal substances, were the first to demonstrate clearly the compound nature of the bacteriolysis. Adding a suspension of anthrax bacilli to frogs' lymph and studying what happened, by prolonged examination under the microscope, they observed that cells possessing granules staining with eosin (amphophil cells) attacked the bacilli, coming into Digitized by Microsoft® 118 INFLAMMATION pt, n contact with them, and, in this process, the granules were seen to be discharged. These cells did not actively ingest the bacilli, but they, while remaining extracellular, showed evidence of degeneration. Only later aud by another form of leucocyte was there, in the frog's lymph, active phagocytosis. In other words, according to them, one set of leucocytes secreted the substances acting upon the bacilli, and prepared these to be ingested by another order of these cells. It must be admitted that these observers introduced not a little confusion by speaking of certain cells as eosinophilous, which, as a matter of fact, correspond in most respects to the neutrophil and amphophil poly- morphonuclears of the mammal, to cells which in higher animals are definitely phagocytic. Mesuil and others have been unable to confirm these observations ; but then they have not repeated Kanthack and Hardy's experiments according to the lines laid down by them ; they have attempted other methods. It must be admitted that in the frog the experiment does not always succeed. I have, however, made and seen pre- parations in which this loss of granulation and coincident degeneration of the bacilli could not be denied. We have not been able to convince ourselves that in the mammal the coarsely granular eosinophil possesses a like excretory function, although Kanthack and Hardy con- vinced themselves that this was the case. In his last confirmatory article upon this subject Hardy (45) calls attention to the fact that after contact with bacilli the coarsely granular oxyphil cells of the frog are diminished in size, and, -what is more, that as the cells crawl over chains of bacilli they leave behind them a slime. Bacilli coated with such a slime never grow. Beckton (56) and others have of late called renewed attention to the similarity in size and staining properties between the Digitized by Microsoft® CM. XIV CELLULO-HUMOEAL HYPOTHESIS 119 granules of eosinophils and lymphocytes and the granules of known secretory cells. The observations of Durham and others indicate a little -understood alteration in bacteria preparatory to ingestion, which, indeed, would suggest that the leucocytes of mammals do afford some preparatory secretion. If, for example, a relatively abundant suspension of actively motile but not highly virulent bacilli be introduced into the peritoneal cavity of an untreated guinea-pig and a drop of the peritoneal Fig. 14. — Leucocytes from peritoneal cavity of guinea-pig into which a microbe of low virulence (Sanarelli's " Versailles " vibrio) has been inoculated, to show "hedge- hog" appearance around the mononuclear hyaline cellrt (a). The eosinophils lb) and the lymphocytes (c) were not affected (the polymorphonuclear — not shown — to a less extent than the hyalines). — After Durham. exudate be examined, it is noted at a certain period that while many of the bacilli are moving freely in the fluid, and may impinge with impunity upon the lymphocytes and eosinophil cells present, those that come into contact with the hyaline mononuclears become arrested and motionless, and the individual leucocytes may be seen taking on a " hedgehog " appearance, the immobilised bacteria adhering by one end to the leucocyte. This adhesion and immobilisa- tion, prior to ingestion, cannot, I think, be explained except by presupposing the existence of a zone of diffusible material discharged from these cells and having a prepara- tory action upon the bacilli. Putting all the facts together, Digitized by Microsoft® 120 INFLAMMATION pt. n it would seem that, under certain conditions, some pre- paratory or intermediary substances are separated from leucocytes of one or other order which aid in the process of phagocytosis, hut the evidence is very far from con- clusive that all the preparatory sidistances are of leucocytic origin. Digitized by Microsoft® CHAPTEE XV SUMMARY I AM thus led to modify Metchnikoff's conception of the mode of action of the leucocytes to some extent, and to believe that the following more nearly represents the state of our knowledge. 1. Phagocytosis — the process of ingestion and diges- tion on the part of the cells of the organism — is the factor most generally involved in the destruction of pathogenic organisms within the system ; both fixed cells, like those of the endothelium, and certain orders of free cells — leucocytes — can manifest this property. 2. Where the cells are able to take up living bacteria, these bacteria have, in most cases, to be subjected to an extracellular action by substances present in the surrounding medium (opsonins) prior to digestion. 3. Bacteria may also undergo destruction without phagocytosis taking place. Where this is the case, the bacteriolytic substance (cytase) is liberated into the medium upon the death and disintegration of cells that are potentially phagocytes. It, however, cannot act without the intervention of a second intermediary body (fixateur) present in the medium. 4. Whether leucocytes and other cells of the body can actively secrete the bacteriolytic substance when stimulated, must be left an open question ; it must, 121 Digitized by Microsoft® 122 INFLAMMATION" pt. n however, be • recognised that certain leucocytes secrete and discharge substances which, if not directly bacterio- lytic, are preparatory to and essential for the destruction of the bacteria. I have so far utilised Metchnikoff's terminology, using the term " cytase " for the intracellular bacteriolytic substances and, thereby, tacitly accepting the view that these bodies are ferments (the termination " -ase " being the conventional method to signify an enzyme). This is the view of the French school of bacteriologists generally. How far is this accurate ? Other workers are by no means convinced that this is their nature. Pfeiffer and Ehrlich ^ regard the intermediary body or amboceptor as the ferment ; and there is much to be said in favour of this view, but, so long as the nature of enzyme action is not clearly understood, so long as it is currently accepted that, in organic fermentations, only two factors are involved, for so long must there be confusion regarding what is the true ferment or enzyme. As a matter of fact, it would seem that in all organic enzyme action for the development of the complete cycle there are at least three factors requisite, and we have to decide which of these three is the ferment. The realisation that three factors are and must be involved immediately aids our comprehension of the facts here brought forward, and renders it easy to grasp the otherwise most puzzling order of affairs presented in the co-existence and mutual ' " Da unter dem Eintiuss des Addiments [intermediary body) Erschei- mmgen auftreten, die man mit Pfeiffer als der Verdauung analog anselieii mnss, so werden. wir nicht fehlgehen, wenn wir dem Addiment den Charaktev eines Verdauungsfermentes vindizieren." — Ehrlich imd Morgen- roth, tjber Haemolysin. 1. Mitteil. Gesammelte Arheiten von Ehrlich, p. 12. It is, however, but right to state that in moie recent communica- tions Ehrlich appears studiously to avoid any definite comparison between the bodies concerned in the production of immunity and the digestive and other ferments. I gather that at present he maintains an open mind in the matter. Digitized by Microsoft® SUMMARY 123 action of the amboceptors and complements, of fixateurs and cytases, opsonins, lysins, et hoc genus omne. The ferments of the body should not be looked upon as a special group of chemical compounds, but, on the contrary, enzyme action should be viewed as a property of a series of substances possibly of very different chemical composition. This view was seriously discussed by Woodhead (128) many years ago. The study of the catalytic action of finely divided platinum, of manganese dioxide, etc., supports this view. I am thus inclined to Fig. 1j. — Diagram to illustrate the conception regarding ferment action and its application to the side-chain hypothesis of immunity. FS, molecule of ferment- escible substance with side-chains ; FR, molecule of fermentator ; F, ferment ; F^ F|i, etc., the successive stages in the action of the ferment. consider that the ferments, or bodies presenting enzyme action, may be regarded as a certain order of unsatisfied molecules, which enter into combination with certain other molecules in the surrounding medium for which they have affinity ; a chemical action takes place resulting in the enzyme becoming attached to certain atom groups of the fermentescible molecule. It is not even necessary to suppose that as the result of this chemical action the atom groups are immediately de- tached. So soon as this union takes place, the enzyme molecule becomes satisfied, and, were there no other substances present to disturb the equilibrium, further Digitized by Microsoft® 124 INFLAMMATION pt. n action would cease. For ferment action to continue there must be some third substance present, which we may term the fermentator or complement, having an affinity for the atom-group represented by the ferment plus side -chain, or atom -group, of the fermentescible substance. As the result of its presence, a second union takes place, and what had been the unsatisfied atom- group of the fermentescible substance of the above com- pound, becomes now attached to and combined with the fermentator. The ferment becomes free, once more unsatisfied, and ready to act again on the fermentescible substance. We may go farther and suppose that the atom-group or side-chain of the fermentator, thus modified by combination with the atom-group from the ferment- escible substance, may either remain attached to the fermentator (complement) or become liberated as a separate entity.^ According to this conception of ferment action, which is the ferment — the intermediary body (fixateur) or the lysin, complement or cytase ? Clearly, I think, the former ; the cytase can only be regarded as the fermentator, the substance essential for the final act in the process. And this view is supported by Wright's phenomenon, in which the bacterial bodies must have the intermediary body (opsonin) in association with them before they can be acted upon by the cells. Possibly it is a matter of convention which we shall term the enzyme or ferment, whether the intermediary body or the third substance essential for the completion of the process. Yet it seems more just that the active factor in the process should receive the name ; just as, with Pawlow and Bayliss and Starling (129), and in opposi- tion to Metchnikoff and Delezenne (130), I would lay 1 I have expanded this conception of enzyme action in my Principles of Pathology, vol. i. p. 58. Digitized by Microsoft® CH. XV SUMMAEY • 125 down that in tryptic digestion the enterokinase is the true ferment, and would regard the trypsinogen as the fermentator. And thus, to sum up, I find myself in harmony with Pfeiffer and Ehrlich in regarding the amboceptor or intermediary body as the ferment, and, in place of speaking of the cytase of the phagocytes, would speak of the cytolysin or the bacteriolysin. To complete this section I will here add other con- clusions deduced from a study of the later stages of inflammation and discussed in a later chapter ("Upon the part played by the fixed cells in the Inflammatory Process "), viz. : — 5. In the later stages of inflammation the growing fibroblasts may often be seen to contain leucocytes in process of digestion. Presumably, therefore, a certain number subserve nutrition. 6. Others are, in certain cases, recognisable in the lymph-spaces outside the inflammatory focus, containing the debris of dead tissue. Emigration can therefore occur as well as immigration. 7. The process of development of wandering into fixed cells has been observed ; cells of what are here termed the hsematogenous type have never been observed to become thus converted ; the histogenous alone would seem able to undergo the change. 8. The contrary process of development of wandering cells from degenerating tissue (muscle -fibres) has also been recorded by more than one observer. Digitized by Microsoft® II._THE INFLAMMATOKY EXUDATION CHAPTER XVI THE FLUID OF THE EXUDATE Whenever injury to the tissues leads to vascular dilata- tion there is an increased effusion of fluid from the blood. The extent of this effusion varies greatly ; it varies vfith the tissue affected, the state of the organism, and the quality and nature of the irritant. Dense tissue permits of little exudation, while loose vascular tissue, under the action of au irritant of no great intensity, may undergo great exudative swelling. There is, for instance, a peculiar liability in serous and cutaneous surfaces (or more truly in subserous and dermal layers), when inflamed, to manifest abundant exudation. Their vascularity and the slight external resistance would appear to explain this liability. There is a like tendency to abundant exudation from mucous surfaces, though here to a large extent, so long as the covering epithelium is not destroyed, the exudation is governed — i.e. partakes of the nature of an excretion, abundant mucus from the cells being also discharged, and is not extreme. With destruction of the covering epithelium it may become profuse ; choleraic diarrhoea is perhaps the most pro- nounced case of exudation in the human organism. That some general state of the organism is a factor concerned 126 Digitized by Microsoft® CH. XVI FLUID OF THE EXUDATE 127 is seen when virulent anthrax bacilli are inoculated subcutaneously into an ordinary rabbit and into one that has been rendered immune : in the former the exudation is of a serous nature, in the latter little fluid is exuded from the vessels — a clear indication that, in the development of the immune state, not merely the leucocytes, but also the capillary v^alls, at the least, become altered in their behaviour to the toxins. The effect of the quality of the irritant is observable upon comparison of the results of inoculation of various microbes. Some cause little exudation of fluid. These are in general of low pathogenic quality, but not always ; certain virulent microbes (such as those of tetanus) lead, when inoculated, to relatively little effusion of fluid from the vessels. On the other hand, it may be stated definitely that where in a moderately dense tissue the injection of a pure culture of a micro- organism leads to well-marked exudation, the micro- organism is of high virulence. Can any meaning be ascribed to this effusion, or, to express the same idea in words which shall not offend those who fear the semblance of teleological ascriptions, has the increased pouring out of fluid into the tissues as the result of irritation been of proved benefit to the species, so that those individuals have survived who have manifested this reaction and have conveyed it to their offspring ? Is it an attempt at increased nutrition in the injured region ? It has been suggested, in accordance with Virchow's conception of inflammation, that the injury, stimulating the surrounding fixed cells, leads to increased local metabolism ; and that the exudation is a means of bringing to the region the increased nourish- ment demanded by the increased cellular activity. But inasmuch as exudation is most marked in those cases where there is most profound and rapid cell destruction, Digitized by Microsoft® 128 INFLAMMATION pt. n and again at the early stage of the inflammatory reaction, when evidences of growth and proliferation of the fixed cells of the region may be, and most often are, wholly wanting, this view can scarcely be upheld. Yet at a later period of the process, and again in chronic inflamma- tion, the overgrowth of the connective-tissue cells would appear to stand in some relationship to the over-nutrition caused by the continued dilatation of the vessels and the pouring out of excessive lymph into the tissues. It must, however, be admitted that the exact relationship subsist- ing between nutrition and cell overgrowth is still a matter of debate among pathologists. That the exudation exerts a " flushing-out " action is very evident in many cases. Thus the inflammation induced by plunging an animal's leg into hot water is accompanied by great increase in the amount of lymph obtainable from the efferent lymphatics of the part. Experimentally it may be shown (Samuel (131) and others) that seven to eight times as much lymph may drain away from an inflamed as from an uninflamed region. It is shown also by the presence of streptococci in the lymph channels outside the area of acute in- flammation in erysipelas, by the frequent implication of the nearest lymph-glands in suppurative disturbances, and by the appearance of lesions, due to the direct action of bacterial products, in organs far removed from the focus of bacterial proliferation in such diseases as diphtheria and tetanus, wherein, as a rule, the bacteria remain strictly localised. It is clear that the exudation into an inflamed area may be much in excess of the normal transudation ; that it can accomplish a removal of irritant matters. It is clear also, from more than one of the examples given above, that a process which may be beneficial to the region of injury may be harmful to the system as a whole. Digitized by Microsoft® CH. XVI FLUID OF THE EXUDATE 129 Study of the " flushing-out " effects of the inflammatory exudate affords, in fact, a good object-lesson as to how far the reaction to injury is to be regarded as purposive. Yet we are forced to see that there is a certain amount of adaptation. Where the irritant can be conveyed to the exterior an abundant exudative inflammation generally occurs — an abundant flushing ; where it can be conveyed into one of the body cavities the same holds good ; but here a mechanism is often called into action (deposit of fibrin) whereby the exudate with its contained irritants is held within the serous cavity for days and weeks after all signs of active inflammation have subsided. The organism, that is to say, would seem to restrain its drainage to the general lymphatic system. Where the irritant is merely the product of tissue-change the profuse exudate is rapidly conveyed away ; where, on the other hand, the injury is of bacterial origin, the passage of lymph from the focus of inflammation is, generally speaking, not nearly so free ; it is of thicker consistency and drains away slowly. In short, as I have already indicated, where the microbe is not too virulent a cellular rather than a serous inflammation is produced ; and in place of abundant flushing an increased antibacterial and antitoxic action of the exuded lymph comes into play. But besides the mere " flushing-out '' the exudation has often another effect, namely, dilution of the irritant and reduction of its injurious properties, so that it acts with lessened force upon the tissues, and permits the wandering cells to be attracted to the region where they may exert their functions. Where a comparatively mild physical irritant leads to abundant exudation the flushing- out action appears to be in the ascendant, where microbic irritants cause great local inflammatory oedema, judging from the less extensive lymph flow from the region, the diluent action must be regarded as the more important. K Digitized by Microsoft® 130 INFLAMMATION m. n I have already pointed out that a relation may be traced between the intensity of bacterial irritation and the extent of the exudation. In short, there may be a great exudation under two apparently opposed conditions : in the presence of comparatively mild physical irritants, and in that of severe bacterial irritants. In the former case it more especially subserves removal, in the latter dilution of the poison. That in general the exudate exercises a beneficial effect upon the process of an actite or subacute inflamma- tion, and that in general this is inadequate rather than excessive has been brought home to us of recent years by the remarkable success which has followed Bier's method of treatment (132), when properly carried out. This treatment consists in the production of a moderate grade of increased hyperasmia in the affected part whether (1) by the application of compressing bandages above the part, so that the free return of venous blood is obstructed, (2) by cupping, so that the lessened pressure causes determination of blood to the part, or (3) by the local application of heat as from electric or hot air baths, lead- ing to increased vascular dilatation. All these means, indeed, bring about dilatation of the capillaries, thinning of their walls, and increased pouriug out of fluid into the tissues. The swelling and redness of the part increase, but the patient benefits. Care, it is true, has to be taken and each individual case treated upon its merits ; there must also be alternation of periods of treatment and rest. If properly carried out, as the part becomes swollen the sense of local pain disappears, and it is replaced by a feeling of general well-being, the inflammation ceases to extend, and actual absorption takes place of the inflammatory products. How does this treatment bring about its good effects ? Since corresponding results are gained whether we slow Digitized by Microsoft® CH. XVI FLUID OF THE EXUDATE 131 the circulation by compression or increase it by the local application of heat, it seems scarce likely that increased passage of leucocytes into the part is the essential process. On the other hand all these methods favour the increased passage of fluid exudate into the affected tissue. It is to this that the good effects are to be ascribed, more particularly to dilution of the irritant and conveyance to the part of an increased amount of antibodies. We can to some extent harmonise the good effects gained by Bier by his treatment with those coincidentally gained by Sir A. E. Wright in his opsonic treatment,^ by supposing that increase in the exudate means increased amount of opsonins brought to bear upon the bacteria setting up the inflammation whereby these are prepared for ingestion by the leucocytes present in the inflamed area. Cer- tainly the exudate contains opsonins ; these pass, that is, out of the blood-plasma into the tissues. ^ Wright's treatment cannot be used for very acute cases, but has been found valuable in subacute and recurrent conditions. It is based upon the inoculation, subcutaneous, of accurately graduated amounts of dead cultures of the microbe that has caused the specific form of inflammation. The results of such inoculations are that the "opsonic index" or relative amount of opsonins in the blood-serum (and so in the body fluids) becomes definitely increased, and with this the capacity of the organism to with- stand the growth of the specific microbe. Digitized by Microsoft® CHAPTEE XVII THE SOLIDS OF THE EXUDATE : FIBRIN FORMATION The fuudamental characteristic of inflammatory exudation as compared with ordinary lymph is its richness in pro- teins. Whether we regard lymph as a filtrate pure and simple from the blood, or follow Heidenhain in regarding it as the result of a selective filtration, it is highly probable that in inflammation the exudate approaches in its composition more nearly to the blood -plasma than does ordinary lymph. The dilatation of the capillaries, the consequent thinning of the endothelial layer with, it may be, the opening of some lacunse between the individual cells, and the direct action of the irritant upon these cells, may all be expected to aid the transuda- tion. In this way the amount of protein matter in the lymph may be increased. But equally important must be the addition of proteins due to the breaking down of leucocytes and tissue -cells. I have already discussed this destruction of the cells, and need not here give the evidence of its occurrence. This increase in the solids, mostly proteids, of the exudate, has been well shown by Samuel, by measuring the flow of lymph from the main lymph-channel of the dog's foot. In one such experiment he found that there was discharged in successive periods of three hours : — 1. Untreated foot: 4-0 c.cm. lymph containing 4 to 5 per cent of solids. 132 Digitized by Microsoft® OH. XVII FIBEm FOEMATION 133 2. Poot subjected to venous obstructioii : 28'5 c.cm. of lymph containing 2 to 3 per cent of solids. 3. Foot inflamed: 28-5 c.cm. of lymph containing 7 per cent of solids. The figures in the third case — of inflammation — do not represent the whole exudate. So thick was the lymph that it tended to clot aud obstruct the canula, and there was, in addition, much cedema and swelling of the foot. But obviously, as Ainley Walker (133) points out, from twenty to thirty times more proteid matter may drain away from an inflamed than from a healthy region. lu addition to the proteins the inflammatory lymph may contain other substances worthy of more than pass- ing note. Of these the more important are ferments, the results of proteolysis (notably fibrin and its pre- cursors, nucleo- albumins and albumoses), and in many cases mucin, together with bactericidal substances, and, where bacteria are present, the products of their growth. Various extractives have been noted. Exudates rich in cells and disintegrated tissue-products — pus, for example, — may contain glycogen, fats, and, as Klotz working in my laboratory at McGill University has recently shown (134), a very definite amount of soaps. The presence and amount of these substances depend largely upon the intensity and character of the inflam- mation. Thus the total quantity of proteins, and the proportion of fibrin, albumin, and globulin present, vary within wide limits. The following table ^ of observations made by Halliburton (135) shows well this variation in proteins, and the difference existing between inflammatory exudations and dropsical effusions : — ^ These figures are thoroughly in accord with those of other analyses by Reuss, Hofmann, Mehu, and LetuUe (136). Digitized by Microsoft® 134 INFLAMMATION Pleural Fluid from Sp. Gr. Percentage Quantity of Total Proteid. Pibrin. Serum- globulin. Serum- albumin. Acute pleurisy, Case 1 ,, ,. Case 2 ,, „ Case 3 Hydrothorax . . \ Average of three cases / 1023 1020 1020 1014 5-123 3-4371 5-2018 1-7748 0-016 0-0171 0-1088 0-0086 3-002 1-2406 1-76 0-6137 2-114 1-1895 3-330 1-557 Exudates, as a rule, have an acidity above 10 with decinormal soda solution, using phenol-phthalein as an indicator, transudates under 10. The difference is too slight to be relied upon. Eeuss, Hofmann, and others have shown that the amounts of solids and extractives vary very slightly ; it is the albuminous matters which mainly determine the variations in the specific gravity. The factors determining the amount of albumin are many. Thus, as a general rule, more albumin will be found in a pleural exudate than in a peritoneal exudate. Some observers, however, place peritoneal exudate first in order. The pericardial and the sub- cutaneous come next. It has been noted, further, that the specific gravity and amount of albumin are somewhat higher in right-sided pleurisies than in left (Berheim and Brunting). The amount of albumin in the blood is also a factor. Thus in anaemia or hydrsemia the specific gravity of exudates is lowered. Other factors are also given ; among them the not infrequent combination of mechanical effusion — or obstruction — with active inflammation. The most im- portant of all -would appear to be the extent of irrita- tion of the affected part. Thus, in four cases of pleurisy, Euneberg compared the amount of albumin found in the pleural fluid with that present in acute blisters produced on the patients by cantharides ; the Digitized by Microsoft® CH. XVII FIBEIN FOEMATION 135 average of the former was 5'43, of the latter ,Q-2 per cent; without exception, the percentage in the blister- fluid was found the higher. It may be laid down (Miller (137)) that fluids with the specific gravity of 1018 or higher, with at least 4 per cent of albumin, are of inflam- matory origin; of from 1010 to 1015, with albumin up to 3 per cent, are due to venous stasis ; of less than 1010, with albumin under 1 per cent, are due to hydrtemic conditions. The Cells of the Exudate. — Much study has, of late years, been devoted to cytodiagnosis, to the diagnosis of inflammatory and other conditions by a study of the cells present in the removed fluids. It cannot, however, be said that, for our present purposes, much has been elicited beyond this, that abundant polymorphonuclears indicate an active inflammation ; a preponderance of lymphocytes, either a tuberculous infection or sub-acute inflammation of other nature of some little duration, though it has also been noted that in the early stages of a tuberculous inflammation {e.g. in a rapidly developing tuberculous pleurisy) there may also be an abundance of polymorphonuclears. Fibrin. — Between the amount of flbrin present in exudations and the amount of peptones there is an inverse ratio. Peptones are especially developed in connexion with suppurative inflammation ; and the more an inflammation tends to be suppurative the greater is the breaking down of the fibrin, as also of fixed and wandering cells, and the more evident the production of peptones, or more correctly of albumoses, until in chronic abscess - formation of fair extent these pass into the general circulation, and are excreted and recognisable in the urine. Into the discussion of the mode of formation of fibrin I need not enter here, intimately connected as the Digitized by Microsoft® 136 INFLAMMATION pt. ii subject is with the inflammatory process. The greater text-books of Physiology enter exhaustively into the matter. Suffice it to say that, as in the blood, a direct relationship is made out between the breaking down of leucocytes and the development of this substance in inflammatory exudations. It is in connexion with inflammation affecting serous and epithelial surfaces ^ that fibrin is more clearly recognisable, forming, it may be, thick coatings of the badly named " inflammatory lymph " over the inflamed surfaces. This deposit is in all respects comparable to the formation of thrombi in the blood-vessels (138). Here, as there, the deposit occurs only when the endothelium has undergone destruction and the roughened sub-endothelial tissues are exposed And here also the fibrin may be deposited either in filamentous or homo- geneous and hyaline form according to circumstances. How far the blood-platelets are involved in the production of inflammatory fibrin is a matter deserving further study. The above statement gives the general consensus of opinion among pathologists of the present time regarding the mode of origin of inflammatory fibrin. And yet this view has been vigorously opposed by Neumann (139), at least as regards pseudo-membranous inflam- mation. According to him, careful examination of fibrinous inflammation of the serosa and of diphtheritic inflammation of the mucous membranes shows that the deposit of fibrin does not lie upon, but under, the endothelium or epithelium. The statements of other observers (Marchand, Orth, Ziegler (140)) that endothelial cells can be seen here and there still remaining under the fibrin, he strongly controverts ; the cells so seen ^ Of epithelial surfaces, more especially those covered by a single cell layer, as notably the pulmonary alveoli. Digitized by Microsoft® OH. XVII FIBEIN FOEMATION 137 are, he declares, swollen connective-tissue cells, and the hyaline glistening bands of fibrin are seen to be directly continuous with the connective-tissue fibrils ; the bands of fibrin, in short, are derived from, and are a modification of, the swollen and altered connective - tissue fibrillse. This change Neumann terms " fibrinoid degeneration " of the connective tissue. He admits that, in acute cases free from connective - tissue proliferation, the fibrin is more probably the result of exudation. Now it is quite true that there are cases in which one cannot say certainly what is the nature of the cells seen under the fibrin ; yet there are other cases in which there cannot be a doubt as to their endothelial nature. As Lubarsch (71) points out, this can be proved experimentally by causing a minimal acute local peritonitis, by simply pulling out a loop of intestine, pinching it with sterile forceps, and replacing it. If the animal be killed, in thirty-six hours small spots may be found here and there, which are covered with a finely granular, scarcely visible deposit of fibrin ; in such local deposits a continuous layer of endothelial cells can be made out passing well under the fibrin, which is pure exudate. Neumann's layer of endothelium covering the false membrane certainly exists in several cases, but it is clearly of secondary development. Gay lord (141), who made a full study of the subject under Orth, has shown clearly that after introducing fibrin or fibrin-forming fluids into the serous cavities, the endothelium proliferates and covers over this foreign fibrin, sometimes before any signs of organisation appear in the mass. Undoubtedly connective tissue undergoes a change in the inflammatory area ; the bundles of fibrillse swell, become more hyaline, lose their fibrillar appearance, and form more homo- geneous glistening bands. But this modified connective tissue can generally be distinguished from fibrin proper Digitized by Microsoft® 138 INFLAMMATION pt. h if suitably stained by employing van Gieson's stain, or thionin. The researches of Leo Loeb (142), conducted in my laboratory, possibly throw some light upon this subject. Taking a little lobsters' blood in which coagulation has been delayed by the addition of a solution of adrenalin chloride, and placing this upon a slide, then covering this with a second slide and pulling the one slide over the other so as to exert traction, it can be seen under the microscope that the cells, arranging themselves in rows, become transformed into a system of threads, and here and there the threads can be seen passing through a cell or even through the nucleus of a cell ; the cells often become spindle-shaped and may either be so drawn out that their protoplasm forms long threads, or fine fibrillar threads may be seen actually passing through several cells. Loeb produced a similar transformation into fibrils by traction upon the protoplasm of exploded cells. It is worthy of note that, during either process, the cell - granules disappear, and these fibrillee have staining and other reactions which connect them both with fibrin and with connective tissue. Many of them, for example, stain well by Mallory's connective- tissue stain. In other words, these observations of Loeb favour the view that the conversion of the protoplasm of connective - tissue cells into fibrillse is the result of tension and traction, i.e. of physical agents, and that the same is true also of the development of the threads of fibrin. If the same process be at work in both conditions, there is little wonder that it is difficult to draw a sharp line of distinction between the intra- and extra-cellular process in tissues where both are occurring at the same time. Leaving out of account coagulation- necrosis as not occurring in direct connexion with exudates, it may be Digitized by Microsoft® OH. XVII FIBEIN FOEMATION 139 said that similar fibrin formation is frequently recognisable in connexion with primary inflammation of parenchy- matous tissues. Where there are abundant and disten- sible lymph-channels extensive clotting may be seen in the lymph. This is peculiarly well marked in the con- tagious pneumonia of cattle (contagious pleuro-pneumonia). In acute inflammation of various organs, by appropriate methods of staining, similar formations of threads of fibrin, often starting from cells as centres, may be observed in the tissue spaces. Many years ago Werneck de Aquilar (143) demonstrated the frequent existence of fibrin in acute tubercular processes. The beneficial effects of fibrin formation in serous cavities have been rendered abundantly manifest by the increase in abdominal surgery. No one who has followed any considerable number of operations for appendicitis can have failed to remark how, in case after case, despite the intricacy of the intestinal coils and their mobility, the strongly irritant matter produced by gangrene of the appendix, or oozing through perforations in it, is restricted within a relatively small space by the surrounding fibrinous adhesions which form rapidly between the intestinal loops. By this means alone the peritonitis is restricted and " regional," instead of being generalised from the onset. Even when inflammation (as in peri- carditis) affects the whole extent of a serous cavity, the layer of fibrin acts as a protective coat closing the lymphatic " stomata," hindering the free absorption of the morbid material by the lymph- and blood-vessels, and filtering bacteria out of such fluid as does find its way through to the tissues beneath. It is not a little remarkable to call to mind how case after case of purulent pericarditis or purulent pleurisy may be examined in which, despite the intense suppurative disturbance in the serous cavity, the tissues at the other Digitized by Microsoft® 140 INFLAMMATION pt. ii side of the deposit of fibrin — the myocardium or the lung tissue — show little or no tendency to abscess formation. Let there be primary abscess formation or gangrene in the lung, and perforation of the pleura and pleurisy may supervene : generalised pleurisy, however intense, does not lead to this unless complicated by other disease. Let there be primary or metastatic abscess in the myocardium, then there may be aneurysm and rupture of the heart ; yet such rupture produced by extension inwards of a purulent pericarditis is of the utmost rarity. Let there be inflammation originating in the submucosa of the intestines, as in enteric fever, and perforation may result ; general peritonitis, while often due to perforation, never — so far as I can find — directly induces that event.^ In all these cases the natural protective layer of the serous surface is removed or gravely injured at a very early stage ; and the layer of fibrin, replacing the serous endo- thelium, forms an effective barrier. I may add that the mucin, extruded so as to form a layer over inflamed mucous surfaces, presents a similar protective action. But here again attention should be called to the fact that, while we can thus recognise an action beneficial to the economy in the laying down of fibrin, the adaptation to the needs of the economy is very far from being perfect, and the ultimate results are even replete with danger. I know of no better example than is to be derived from a study of the great omentum in a series of cases of abdominal disturbance (145). Time and again 1 Where, however, there are localised pockets of pus such perforation may occur, and what I have termed "exogenous perforative ulceration" of the intestines is much commoner than is generally suspected (144). Thus in 700 autopsies in all conditions, I encountered it seventeen times. The conditions favouring the development of the condition are adhesions after general or local peritonitis : formation of a pocket of pus, or abscess, between them ; tension, acting with most effect on a soft walled viscns ; compression, aufemia, and malnutrition of the wall ; lessened vitality ; infection ; ulceration ; perforation. Digitized by Microsoft® CH. XVII FIBEIN FOEMATION 141 we find that this which, with the peristaltic action of the bowels, appears to be in constant movement over their surface, has become attached ■ by fibrinous adhesions over some inflamed area, thereby acting as a plaster or pad, reinforcing a weak point and, by the adhesions, preventing generalised peritoneal infection. From this aspect alone, the great omentum can only be likened to a brooding abdominal providence. But, when these adhesions organise, the omentum, now firmly attached, forms a band or bands of most dangerous import ; now constrict- ing a coil of the intestine and so causing obstruction, or kinking the bowel, or leading to internal hernia and volvulus. In short, the late results of adhesions may be very serious. The fibrin so thrown out, while it may (1) be dissolved by the action of bacterial products, or (2) undergo complete absorption by the cells and fluids of the body with restitutio ad integrum of the affected areas, may also (3) form a frame-work upon which new tissue- growth occurs with replacement by organised connective tissue. This new tissue -formation in inflammation we shall discuss later. Passing now to the ferments and ferment-like bodies present in the exudate, I may briefly state that these are not only generated and excreted by the pathogenic bacteria present, but are liberated by the breaking down of the wandering cells. Abundant evidence of the existence of bacterial ferments capable of acting upon proteids, gelatine, sugars, etc., is supplied by the study of the growth of these microbes outside the body. No less than six such enzymes are said to be produced by the B. pyocyaneus, for it has been shown that dead cultures of this organism will liquefy gelatine, coagulate milk, and redissolve the coagulum, invert cane sugar, split up fats, and decompose proteids. That ferments also originate Digitized by Microsoft® 142 INFLAMMATION pt. n from the wandering cells has been demonstrated by Leber (34), who, placing pieces of copper in the anterior chamber of the eye, thereby produced a purulent collec- tion devoid of microbes, and showed that the exudate was capable of digesting proteid matter. In this the leucocytes do not differ from the other cells comprising the organism. There have of late years been abundant observations by Salkowski (146), Jacoby (147), Conradi (148), and many others, upon the phenomena of autolysis, or the self-digestion of liver, muscle, and in fact most tissues, in which it has been shown that without bacterial action, but by the action of their own juices, the cells are able to digest and disintegrate themselves. Only in the inflammatory exudate the conditions favouring such self- digestion would seem to be markedly augmented. Mtiller (149) has shown that pus has a strong digestive action upon dead tissues, and to such autolytic action is now ascribed, on what appear to be convincing grounds, the resolution of the pneumonic exudate. Flexner has recently demonstrated that autolysis also occurs among bacteria. Cultures of the micrococcus of epidemic cerebro-spinal meningitis are very short lived. A smear from such cultures thirty hours old may show abundant typical diplococci ; the same cultures a few hours later may show not a single coccus. Dying they have digested themselves. Eegarding the ferments, Opie (150), setting up non-bacterial inflammation by injections of turpentine, has demonstrated the existence of two proteolytic enzymes present in greater or lesser amount, according to the nature of the predominating cells of the exudate ; the one first described by Friedrich Miiller is peculiar to the polynuclear leucocytes, and is most efficient in a weakly alkaline medium. The second present in the mono- nuclear leucocytes digests in the presence of acid ; it resembles the so-called autolytic enzyme present in Digitized by Microsoft® CH. XVII FIBEIN FORMATION 143 almost all the tissues of the body — the enzyme which leads removed tissues to digest themselves in the absence of any bacteria of putrefaction. But at the same time he has determined that in the serum of the exudate there exists an " anti-enzyme," or body arresting the activity of these enzymes. The conclusion is that digestion of fibrin and of dead cells is not apt to occur until either the leucocytes are present in overwhelming amounts (as in thick pus), or where, with arrest of the inflammation, the fluid exudate, and with it the anti-enzyme, becomes drained off. He found, for example, that a single injec- tion of turpentine into the pleural cavity led to a fibrinous exudate ; repeated injections, by causing abundant poly- nuclear leucocytosis, converted the fibrinous into a purulent exudation, with evidence of softening and disintegration of the fibrin already laid down ; as also that when he had established a serous inflammation, complete aspiration of the fluid was followed by the appearance of localised empyema or suppuration. It is evident that in the absence of the antibody of the serum the enzymes left adherent to the fibrin over the pleural surfaces cause active proteolysis, and that the products are irritative, attracting further leucocytes to the part. At autopsy I have been impressed a.t the frequent tendency to the formation of localised abscesses in cases of general peri- tonitis that have been operated on, the fluid being drained away. At operation these cases have been found to be of the serous type. Now they have become purulent. These observations of Opie upon the existence of a body in the serous exudate inhibiting the proteolytic activity of the leucocytic products suggest that it is not always advisable to perform complete paracentesis, i.e. complete removal of serous inflammatory fluids, however wise it may be to remove the denser purulent collections as fully as possible. Digitized by Microsoft® 144 INFLAMMATION pt. n It would seem, therefore, that, more especially in pyogenic inflammation, the removal of dead tissue cells and dead leucocytes may, to a large extent, be due to the action of the inflammatory exudate, apart from any phagocytic action on the part of living active cells ; although this also comes often into play. The bactericidal substances present in the inflamma- tory exudate have already been considered. We have abundant evidence that substances capable either of destroying microbes or of hindering their growth are present therein. Summary. — -To sum up what is known concerning the inflammatory exudate, it may be said — 1. That the exudate varies in amount and in character with (a) the nature and intensity of the irritant, (5) the condition of the organism, (c) the region of irritation. 2. That while it undoubtedly augments the nutrition of the affected region, increased nutrition at the early stage of an acute inflammatory process would not seem to be of benefit or to play any important part. .At a later stage and in chronic inflammation the increased nutrition possibly aids the hyperplasia. 3. That in many cases the exudate exerts a beneficial action by flushing out the injured area. But this same flushing-out, by distributing the microbic irritants, may also be harmful to the economy. 4. That the exudate plays an important part in diluting the irritant. 5. That the development of fibrin in certain inflam- matory exudates is associated with the breaking down of the wandering cells, and is of manifest benefit in so far as it circumscribes the inflamed area, and prevents the passage of morbid material outwards. Here again the action, by favouring the development of organised adhesions, may be deleterious. Digitized by Microsoft® OH. xvn FIBEIN FOEMATION 145 6. That the exudate may possess digestive functions, causing the production of albumoses and other products of nitrogenous disintegration ; the ferments being developed from the cells alone when the exudate is aseptic, from these and . the microbes together when pathogenic microbes are present. 7. That the exudate may further contain substances, generated by the cells, capable of hindering bacterial growth, and of destroying pathogenic microbes. Digitized by Microsoft® III.— THE BLOOD-VESSELS CHAPTEE XVIII THE PART PLAYED BY BLOOD-VESSELS The study of the action and function of the leucocytes in inflammation has profoundly modified our conception of the inflammatory process. When the leucocytes were regarded as purely passive agents, and their diapedesis as purely secondary to modified conditions of the blood- current and of the vascular walls, Cohnheim's hypothesis was that most generally accepted ; this hypothesis regarded the changes in the vessels as of the first importance. Thus it was that for several years our attention was mainly concentrated upon the determina- tion of the various changes of the vessel-walls, and of the mechanism whereby these changes were brought about. Nowadays less attention is directed to this side of the inflammatory process, and it may be said that during the last ten years little advance has been made in determin- ing the mechanism of the dilatation that accompanies inflammation. The subject, indeed, is beset with difficulties. It is most difficult to observe the changes that occur in the cells forming the endothelium of the congested vessels ; we are still, for instance, far from being sure whether the opinion of Arnold (151) is 146 Digitized by Microsoft® oH.xvm PART PLAYED BY BLOOD-VESSELS 147 correct, namely, that the leucocytes, and, it may be, a large portion of the exuded plasma, find their way out through the dilated stomata between the endothelial cells ; or whether the leucocytes pass directly through these cells as one soap bubble may be passed through another. And when we come to discuss whether the inflammatory exudation be a filtration, or whether, on the other hand, it be more of the nature of an excretion, or what may be' termed a selective filtration — certain components of the blood-plasma being permitted to pass through, while others are withheld — we are met with the difficulty that, of the extravasated leucocytes, a varying proportion undergo rapid destruction and dissolution. Thus, in analysing the inflammatory serum, we are not dealing simply with the extravasated fluid, but with a fluid which in addition contains proteid and other constituents derived largely from broken-down white corpuscles, and in part, it may be, from the modified cells of the inflamed area. Though Arnold's observations upon the altered con- dition of the vascular endothelium in inflammation appear at first very convincing, upon further study they seem at most to indicate that witli dilatation of the vessels there is an increase in the size of the spaces between the endothelial cells. They do not, however, prove that these are other than virtual spaces filled with intercellular substance ; and indeed Arnold himself came eventually to the conclusion that some such substance was present. That viscid, gelatinous substances injected into the circulation may be detected passing through these stigmata is not a proof that the spaces are actual ; all it proves is that the walls are weaker in these regions ; it must be remembered that increased force and increased intravascular pressure are necessary to promote the passage of the injected mass along the vessels. The Digitized by Microsoft® 148 INFLAMMATION pt. n passage of the mass through the walls may therefore be an " artefact." Kolossow (152) has demonstrated that the endothelial cells of the intima of vessels are not absolutely inde- pendent units, and that they are connected one with the other by numerous fine brides or bridges of cytoplasm. Between these bridges are the stigmata ; stomata — larger spaces — are not normally present between capillary endothelial cells. He holds that, normally, the cuticular portions of the cells are in apposition, but that with distension the stigmata from being potential become actual spaces, through which the migration of leucocytes and the escape of fluid may take place. There is this further difficulty in the assumption that these are actual spaces — that in acute inflammation the exuded iluid contains a smaller quantity of proteids than does the blood-plasma. It is true, no doubt, that the stigmata are so small they may possibly act like the pores of a filter, and consequently may not permit the free passage of certain constituents of blood-plasma. To enter into the large subject of the nature of lymph would be to pass too far afield ; I can here only say that taking into consideration the afcundant evidence we possess of the activity of endothelial cells — influenced also, it may be, by loyalty to my old master Heidenhain — I have not become convinced by the brilliant researches of Starling that these cells have no selective activity, governing to some considerable extent the quality and the quantity of the exudate. We have not a little evidence that these cells play an important part in the vascular phenomena of inflammation. To their power of taking up microbes and acting as phagocytes I have already referred ; into their connexion with the slowing of the blood-stream I shall enter later. Here I would point out that microscopically these cells Digitized by Microsoft® OH. xviii PAET PLAYED BY BLOOD-VESSELS 149 can be seen to alter during the inflammatory process ; they become enlarged and project into the lumen of the smaller vessels, and in my experience this enlargement affects not only the cell-bodies, but also the nuclei, which at the same time would seem to contain more chromatin and to stain more intensely. In eases of chronic inflammation the enlargement is followed by prolifera- tion, notably in the arterioles and capillaries, — a process which may lead to the ultimate occlusion of these small vessels. And in acute inflammation mitosis is to be seen occurring in these endothelial cells at an earlier period than in the surrounding tissues. A further and very important process intimately connected with the proliferation of the endothelium of the capillaries is the formation of new vessels as the result of continued inflammation. It is true that Eindfleisch (153) and others have described this as being brought about by vaso-formative cells situated externally to the vessels ; and that others have advanced so far as to suggest that there are cells in the newly-forming granulation-tissue which become hollowed out and gain attachment to the pre-existing capillaries in a manner wholly similar to that observable in the vascular zone of the embryo of the chick. The search for the earliest signs of new capillaries is a matter of some difficulty. I will not peremptorily state that Eindfleisch mistook an arrangement of cells not unfrequently seen in granulation-tissue for stages in the development of new vessels. My own observations coincide with those of Arnold, Ziegler (154), and of the majority of those who have more recently studied the question, and lead me to regard the formation of new capillaries as originating from the endothelium of the vascular loops already in existence. This, I hold, must now be regarded as settled. Digitized by Microsoft® 150 INFLAMMATION pt. n The first step in the process is often recognisable, in cases of pleurisy and pericarditis, in the projection of loops of pre-existing capillaries beyond the line which indicates where the serous endothelium used to be, and into the fibrinous clot now adherent to the sub- endothelial layer. Such loops are markedly distended, and " point," as it were, at right angles to the denuded surface. A similar pointing or giving way of the wall along the convex margin of the loop is also to be made out not unfrequently in newly-developed capillaries. In these there is not, as might be expected, a thinning of the endothelium along this outer margin, but certain of the cells on the contrary appear large and active. At times a small sharp protrusion of the vessel-wall can be detected in the region of pointing. This is best seen in the capillaries that are themselves but newly formed, and composed of nothing but a layer of young endothelial cells. In this layer the protrusion can be made out to be in direct continuity with the endothelial cells of the region. At first it is solid, but in the later stages it can be seen to be nucleated, and to be growing by pro- liferation of the endothelial cells which thus jut outwards. Even before any further change is noticeable • in this projection from the capillary wall it may be seen to be united with a similar process originating from a neighbouring vascular loop. Finally, it would apppear that the joined processes become hollowed out, and thus are developed into fully formed capillary loops. It seems impossible to make precise observations on the phenomena of new vascular formation in its successive stages. I can but state that these appear to be the steps of the process. By what means the new vascular projections join together to form loops we are ignorant. Metchnikoff suggests that there must be an attraction between the neighbouring projections — achemiotaxis — leading them to Digitized by Microsoft® OH. XVIII PART PLAYED BY BLOOD-VESSELS 151 come into apposition ; that chemiotaxis is a factor in the formation of new vessels has been indicated by Council- man (29), who has pointed out that where, in keratitis, the lesion is exactly central these new vessels are seen advancing inwards all around the periphery ; where the lesion is eccentric these form only on the side nearest the lesion. That they do join is very clear to those who have studied granulation-tissue, or have observed the vascular network connecting the previously separated surfaces of a wound. A further function of the vessel-walls is to be seen in the slowing of the blood-current. It is difficult, and in fact impossible, to explain this slowing by altered diameter of the arteries and veins. The alterations observed in the diameters of the vessels of the inflamed area are such as, acting alone, would lead to increased rate of flow. 'Sot, again, is the apparent amount of exudation, and of lymph-flow from the affected part, sufficient to make it probable that (as Wharton Jones (155) first suggested) the slowing is in the main due to the concentration of the blood, relative drying of the corpuscles, and consequent increase of friction ; while this may be an adjuvant we must, I think, find some more potent factor. What this factor is was pointed out long ago by Lord Lister (156), who, in 1858, noticed that, coincident with the slowing of the blood-stream, the corpuscles move sluggishly along the vessel-wall as though attracted by it. He essayed to prove this by an experiment performed previously by Weber (157). He ligatured a frog's leg, then irritated a portion of the web by a little mustard, and found that, although the blood- current had ceased, there was nevertheless an accumulation of corpuscles in the vessels of the irritated area, the corpuscles gliding into the affected region and becoming adherent there. Eyneck (158) has shown that this Digitized by Microsoft® 152 INFLAMMATION pt. h accumulation is not due to increased adhesiveness of the Fig. 16. — Formation of new vessels in inflammatory tissue. (l)Froin a Ziegler's chamber (i.e. one formed of two cover-slips) left in the peritoneal cavity for forcy-eight days. The tissue formed between the cover-slips consists of uninucleated and multi- nucleated formative cells. It is bounded by fully-formed new capillaries, and in the angle between these the solid buds or processes of developing new capillaiies are well seen. (2) Formative (connective tissue) cells in direct connexion with the endothelium of newly-formed capillaries. -From a similar preparation. — Ziegler. red corpuscles, inasmuch as similar slowing and stasis Digitized by Microsoft® CH. xviii PAET PLAYED BY BLOOD-VESSELS 153 may be induced if the blood of the frog's leg be replaced by milk and the web irritated. In this case there is a gradual slowing of the stream of milk and accumulation of the fatty globules in the inflamed area. If, on the other hand, the vascular endothelium be killed by the action of circulating metallic poisons, then he found that no stasis occurred. And in favour of these views of Lord Lister and Eyneck is the fact already noted, that in inflammation the endothelium of the vessel-walls becomes altered, the cells becoming enlarged. With this, as evidenced by the conduct of the white corpuscles, they become more adhesive, and this adhesiveness with the associated increased friction between the vascular walls and contents I regard as the first factor in bringing about the slowing of the blood-stream. Let the current once accelerated be rendered slower by this increased friction, then transudation may accentuate the accumulation of corpuscles. Summary. — While there is very much yet to be learned concerning the part played by the blood-vessels in inflammation, and while our present knowledge of this branch of the subject can only be regarded as very imperfect, the following may, I think, safely be said to epitomise what is known at the present time : — 1. That the vascular walls, and more especially the endothelial cells lining the capillaries, play an active and not a passive part in the inflamed area. 2. These cells have the power of throwing out pseudopodia and of taking up non-motile bacteria. 3. They are larger and more prominent during inflammation than they are under conditions of health. 4. From them are developed the new vascular loops in cases of more chronic inflammation. 5. Their inner surface would seem to become more adhesive in inflammation, and by this, in the first place, Digitized by Microsoft® 154 INFLAMMATION pt. ii to lead to the arrest and adhesion of the leucocytes and red corpuscles. 6. Similarly they would seem to cause an increased resistance to the passage of the blood-current, and thus tend to slow the rate of blood-flow. 7. The slowing of the stream may further be aided by the passage through the walls of increased amounts of fluid from the blood. 8. It is impossible by analysis of the inflammatory exudation to determine whether this be a mere filtrate or be the result of a selective activity of the endothelium. On the whole there appears to be a combination of the two processes. Other properties of the blood-vessels in respect of inflammation will be better discussed in later sections in connexion with the discussions on the part played by the nerves, and on the formation of new tissue. Digitized by Microsoft® CHAPTEE XIX ON THE PASSAGE OF CORPUSCLES OUT OF THE VESSELS By his researches, Cohuheim (1867) forcibly attracted the attention of pathologists to the diapedesis ^ of leucocytes in inflammation — a process which had already been very clearly described years before by W. Addison (159) (1843) and Waller (160) (1846) in England; and yet earlier (though without grasp of the connexion between the diapedesis and inflammation) by Dutrochet (161) in France (1828). Cohnheim recognised the amoeboid nature of the leucocytes, and saw that once outside the vessels they moved actively, but eventually he could not discover that their penetration of the vessel- walls was anything but passive, although twenty years previously Augustus "Waller had clearly described the active nature of the process ; and this failure on Cohnheim's part to recognise the true nature of diapedesis confirmed him yet more strongly in the view that the all-important factors in the inflammatory state were the changes in the vessel- walls, and, it may truly be said, arrested his advance towards a fuller comprehension of the subject. ^ It has been objected that the term "diapedesis " should strictly be employed to denote only the passive transit of red corpuscles out of the vessels. If the word was originally employed in this sense it was an incorrect use : the term clearly indicates an active process — a "footing through " or jumping through. 155 Digitized by Microsoft® 156 INFLAMMATION pt. n It must be acknowledged that there is much which would seem to support this view of the passivity of the leucocytes. No one is prepared to attribute active movements to the red corpuscles, nevertheless in inflam- mation a certain number of these escape through the vessel-walls. In the inflammation affecting some organs, notably the lungs, the number effecting a passage is very considerable. If, then, the red corpuscles emerge passively, why should not the emergence of the white be passive also ? Add to this the very important observa- tions made by Cohnheim, that where the circulation is arrested by compression of the artery there diapedesis ceases. This, if invariably true, would seem to indicate that when once by changes in the vessel the leucocytes adhere to the wall, the further passage through that wall is due to the vis a Urgo of the blood-pressure. This, however, is not a safe deduction to draw from the experiment referred to. When the artery of an inflamed area is compressed the stoppage of the blood- stream not only reduces the pressure, but also affects the quality of the blood and the conditions of the vessel- walls ; moreover, it must profoundly affect the vitality or at least the activity of the contained leucocytes. These considerations alone render the experiment valueless as a proof of the passive nature of the diapedesis. Again the passage outwards of red corpuscles does not occur in the earliest stages of reaction to irritation ; it never precedes the diapedesis of the leucocytes (save where there is gross injury), but follows it. A capillary or small vein in the inflamed frog's web, for example, may be seen wholly filled with corpuscles, the peripheral zone being quite annihilated, and numerous red corpuscles lying in im- mediate contact with the walls ; nevertheless at first leucocytes only emigrate. This difference must be due to some special property of these cells. The leucocytes Digitized by Microsoft® CH. XIX THE PASSAGE OF COEPUSCLES 157 in the blood-stream are not necessarily globular nassive agents, but are capable of independent movement. Leber (34), in his long series of studies, has pointed out that if, with due precautions, a hooked glass tube (closed at its outer end where it catches into the incision in the wall) be inserted into a large vein no thrombosis may be set up around the intravascular portion, and yet, upon removal, a large collection of leucocytes may be found in the tube, attracted by a drop of mercury placed, along with normal salt solution, within it. (Mercury is a substance which within the tissues leads to an accumulation of leucocytes.) Here, then, there must be active attraction and active movement of the leucocytes within the blood - stream. And Lavdowsky (163) has described very exactly what other observers had also, noted, namely, that in inflammation the leucocytes in the outer zone of the blood-stream do not simply adhere passively to the wall, but move back- wards and forwards before they attach themselves and emigrate, as though seeking for a point of less resistance. At times this movement is in a direction opposite to that of the blood-current. Further, Councilman has called attention to the suggestive fact that in the process of migration the nucleus is always directed to the objective point and, with a small surrounding of cytoplasm, is the first part of the cell to pass through the capillary wall. More than one observer has seen a relationship between the labile, broken-up character of the nucleus of polymorphonuclear leucocytes and their function of passage through minute orifices in the capillary walls. If both within and without the vessels the leucocytes can be actively amoeboid, it is strange that they should be passive in the process of diapedesis which to the eye has so characteristically amoeboid an appearance. As above stated, the compression of the artery passing to an inflamed area is in most cases sufficient to arrest Digitized by Microsoft® 158 INFLAMMATION pt. n diapecksis in that area, and I have suggested that this arrest may be due to the altered environment of the leucocytes. Now, if an embryonic form be taken, in v^hich the tissues would seem to possess greater inherent vitality coupled with less sensibility, the arrest does not necessarily occur. Thus, Metchnikoff has noted that diapedesis of the leucocytes can be followed in the tadpole's tail, after the animal has been curarised to such an extent that the heart has ceased to beat and the blood in the capillaries has been brought to a standstill. It is evident, therefore, that with our present know- ledge we must regard the diapedesis of the leucocytes as an active migration, and must look upon the blood- pressure, the disposition of the blood-stream, and the altered condition of the endothelium of the dilated vessels as adjuvants in the process. The slowing of the blood- stream and the diminished pressure in the inflamed capillaries render it more easy for the leucocytes to accumulate close to the vessel-wall ; the dilatation of the vessels and consequent thinning of the walls, with the opening, perhaps, of larger spaces of cement substance or stigmata between the individual endothelial cells, render it more easy for the leucocytes to accomplish the passage ; but the movement from within the capillaries to the tissue- spaces outside is an active process due to amoeboid movement of the leucocytes themselves. The continuity of the vessel-wall once destroyed, other cells — red corpuscles — may be pressed passively through the walls. If this view be accepted, we are bound to look beyond Cohnheim's limit of changes in the vessel-wall for the stimulus which, originating in the area of irritation, acts upon the vessel-wall and the leucocytes in contact with it, and, having first set up changes in the former, so reacts upon the latter that they emigrate ; or, to put it in other words, are attracted out of the capillaries Digitized by Microsoft® CH. XIX THE PASSAGE OF COKPUSCLES ]59 towards the focus of irritation. It has already been shown that the movement of wandering cells in the tissue is due to the attraction of a diffusible product of Fig, 17. — 1. Capillary (inflamed) of frog seen in profile, exhibiting margination of leucocytes, assumption of pear-shaped form, and migration through wall ; a leuco- cyte adherent by long process. 2. A leucocyte in process of diapedesis, showing the pseudopodia in the outer aspect of capillary. From mesentery of rabbit ; also in profile : higher magnification. — Lavdowsky. bacterial growth and of tissue change, and of sundry organic and inorganic materials — the force to which the name of positive chemiotaxis has been given. Chemiotaxis must be invoked to explain the active emigration of the leucocytes from the capillaries, and Digitized by Microsoft® 160 INFLAMMATION pt. n again to explain its cessation under other conditions. Thus, while the exposed mesentery of a frog is a tissue in which diapedesis can be observed with facility under ordinary conditions, if it be washed with a weak solution of quinine, the leucocytes in the vessels remain globular, cease to adhere to the walls, and do not emigrate. This observation, first noted by Binz (164), has been confirmed by others, among whom Disselhorst (165) made out also that, if these same leucocytes be removed from the vessels, they exhibit their usual amoeboid movements. The quinine has not paralysed them, as Binz supposed ; but, as Metchnikoff pointed out, it has neutralised the previous positive attraction, a negative or repulsive chemiotaxis being brought into play. It is difficult to see how these observations can be otherwise explained. The view that diapedesis is an active process gains further support from, and at the same time explains certain interesting observations made by Bouchard (166), Eoger (167), Charrin (168), and Euffer. These observers have independently shown that in sundry instances the results of local injection of virulent cultures are greatly modified if, shortly before or coincidently, the microbes and their products are introduced into the circulation. Thus, as Euffer points out (169), a drop of the culture of the bacillus pyocyaneus inoculated into the anterior chamber of the rabbit's eye leads ordinarily to a great migration of leucocytes — to an acute purulent inflamma- tion. If, however, the toxins produced by this microbe have previously been injected into the circulating blood, no accumulation of leucocytes follows inoculation into the eye. Euffer also extended most suggestively certain observations of Eoger (167). Subcutaneous or intramus- cular inoculation of the rabbit with the bacillus of symptomatic anthrax leads to the production of a local abscess with extensive accumulation of leucocytes. After Digitized by Microsoft® CH. XIX THE PASSAGE OF COEPUSCLES 161 simultaneous injections of fluid containing virulent bacilli and their products into the vein of the ear and the muscles of the hind leg, Euffer found the rabbit dead within fifteen hours, with a huge tumour in the inocu- lated limb. Here, upon examination, the muscle-fibres were found widely separated by fluid exudate, in which there had been great multiplication of the bacilli; but leucocytes were entirely absent. In these two cases we have therefore diapedesis and determination of leucocytes following the purely local action of the toxin ; want of diapedesis and absence of leucocytes when the toxin at the same time circulates in the blood-stream. Wholly in line with these are the observations of Sidler (170). Solution of iodine, injected subcutaneously into the ear of a rabbit, sets up an inflammation characterised by extensive exudation with associated abundant migration of leucocytes into the part. With the injection of 0'05 per cent iodine solution peripherally into ■ the ear vein there is the same or even more extensive fluid exudate, but no leucocytosis. If any large proportion of the leucocytes which find their way to a focus of irritation emerge from the blood-stream, these divergent results are only to be explained by some hypothesis which is capable of reconciling the difference in the action of the leucocytes when they are circulating in normal and in toxin- or irritant-containing blood respectively. Now, the results in these cases are entirely consonant with what we know concerning the sensitiveness and reaction to stimuli not only of unicellular organisms, but also of the higher animals. Organisms, whether lowly or of most complex development, only perceive and react to alteration in their environment when the altera- tion exceeds a definite ratio. Thus, as Pfeiffer has pointed out, a motile bacterium (the " B. termo ") is attracted towards solutions of peptone ; if it be already M Digitized by Microsoft® 162 INFLAMMATION pt. n in a peptone solution, in order for it to be attracted towards and move into a more concentrated solution, this last must be five times as strong as is the former. This is in conformity with the psychophysical law of Weber- Pechner : that sensibility increases in arithmetical ratio when the stimulus or excitation increases in geometrical ratio — or, in other words, reaction is in proportion to the logarithm of the excitation. The only possible explana- tion that I can see of the above observations of Buffer, Eoger, and Sidler is that the passage and want of passage of the leucocytes out of the vessels depends upon the ratio of diffusible bacterial products present in the blood-stream and in the tissues respectively. Where the products are localised at one focus in the tissues, the leucocytes are attracted out of the unaltered blood, and there is active diapedesis ; where there was already a solution of the bacterial products in the blood, the ratio of difference between the percentage amount of toxin in blood and tissue may be insufficient to stimulate the leucocytes ; no diapedesis then ensues. As is well shown in the experiment with symptomatic anthrax, the presence of the bacillus and its products in the circulating blood did not prevent inflammation at the region of local injection ; inflammation and exudation were abundantly manifest — there was, in fact, a more extensive exudation than ever. The irritant — that is to say, the toxic products of the bacilli — at the point of injection was in no wise hindered from exerting effects upon the fixed cells of the vessel-walls, and promoting all the changes in calibre and condition of the walls and in the blood-stream characteristic of inflammation. But with vascular changes, if anything more prominent than in the case where local inoculation alone had been practised, the leucocytes stayed within the vessels. Now the only cause to which we can attribute this abstention of the Digitized by Microsoft® CH. XIX THE PASSAGE OF COEPUSCLES 163 cells from emigration is lack of attraction — certainly not lack of vascular change or lack of blood-pressure. Summary. — We are thus led to the following con- clusions regarding the passage of cells out of the blood- stream into an inflamed area : — 1. The diapedesis of the leucocytes is, as the name implies, an active and not a passive process ; it is due to active amosboid movements on the part of the cells. 2. The stimulus leading to diapedesis is that of positive chemiotaxis. It is the attraction exerted upon the leucocytes by the diffusible substances associated with the irritant. 3. Irritants, if themselves diffusible, or the diffusible substances developed while the irritants are within the tissues, are capable of two separate actions : one direct upon the vessel-walls, leading to vascular changes ; the other through the walls upon the leucocytes, whereby emigration may be induced. 4. These two actions need not (and frequently do not) manifest themselves pari passu. 5. In relation to diapedesis, the dilatation of the vessels, the altered rate of blood -stream, the altered disposal of the corpuscles in the stream, and the modified endothelium, may all be regarded as adjuvants. 6. The passage of red blood corpuscles from the blood- vessels into the inflamed area is passive, due to the blood- pressure and to lack of continuity of the vessel-walls. Such lack of continuity is favoured in many instances by the migration of the leucocytes through the walls. Digitized by Microsoft® IV.— THE NEEVOUS SYSTEM CHAPTEE XX ON THE PART PLAYED BY THE NERVOUS SYSTEM If the vascular changes in inflammation were due to reflex influences proceeding from the central nervous system, and were in fact controlled by the centres in the brain and spinal cord (as has been held by the supporters of neuro-humoral hypotheses), then, in the first place, there should be a rapid and almost immediate response on the part of the vessels of any region on the introduction of an irritant. But this is not by any means constantly observed. Thus, as Cohnheim pointed out, if croton oil be rubbed upon a rabbit's ear, more than an hour may elapse before the first beginnings of hyperEemia can be detected ; yet the inflammation eventually set up may be very intense. In the second place, section of all the nerves passing to any region of the body should have this effect, that injury in the region in question should be unaccompanied by the ordinary vascular reaction. But this is not the case. Divide all the nerves which supply a rabbit's ear, for example, and then injure that ear, either by heat, cold, or inoculation of pathogenic micro-organ- isms, and inflammation manifests itself with all the stages recognisable in an ear with intact nerve -supply. The vascular changes which accompany inflammation can 164 Digitized by Microsoft® OH. XX PAET PLAYED BY NEEVOUS SYSTEM 165 occur, then, independently of any central nervous in- fluences. We can proceed further, and state that regions deprived of their nerve-supply are peculiarly prone to inflammatory changes. But this liability to inflammatory disturbances in such regions is not directly due to the destruction of vasomotor tracts and the cutting off of central influences from the vessels of the part, but is, it would seem, immediately connected with the loss of sensation. Divide the ocular branch of the fifth nerve of a rabbit, and, if the eye be not protected, ulceration and necrosis of the cornea manifest themselves in the course of a few days. Protect the eye, either by bringing the lids together or by placing a shade over it in such a way that dust and foreign particles are prevented from settling upon the surface, and no such ulcerative disturbance manifests itself. From this it is clear that the primary cause of the inflammation is not any trophic change in the region, but is the lack of sensation, wliereby irritant substances are permitted to gain a lodgment upon the outer surface without any attempt being made to remove them. That, in addition, there is a lowered vitality in parts deprived of their nerve-supply, and that this renders those parts a more favourable seat for inflammatory disturbances is more than probable ; nevertheless, this would not seem to be the primary cause of the increased liability to inflammation. This, then, in the first place, is clearly recognisable — ■ that the vascular changes accompanying inflammation can occur independently of central nervous influences. Hence it follows that there must be a peripheral mechan- ism controlling the vessels. It remains, therefore, to determine the nature of this peripheral mechanism : is it wholly under the guidance of peripheral nerve-cells situated in the vessel-walls, or is it, in part at least, idiocellular ? In the present state of our knowledge the Digitized by Microsoft® 166 INFLAMMATION pt. n answer to this question must be guarded. The more carefully the innervation of the various regions is studied, the more clearly is it demonstrated that throughout all the tissues of the body there exists a wonderfully fine and complicated net-work of nerve-filaments with occa- sional isolated ganglion-cells. Yet proof is wanting that this system in connexion with the vessels is sensorimotor. Indeed, so far as regards the heart and ventricular muscle (which may be looked upon as the region of the vascular system wherein the motile portion of the walls has become specially developed), the researches of Eomberg and His lead rather to the conclusion that the peripheral nervous system subserves sensation alone. Nevertheless, there are observations to the contrary. Mall (l7l), for instance, has demonstrated the existence of motor nerves in the portal vein, finding that after ligature of the thoracic aorta stimulation of the splanchnics causes the portal vein to contract until the lumen almost disappears. The portal vein, it is true, has functions differing from those of most other veins ; but this observation renders it possible that some veins, at least, may be modified by central stimuli in the course of the inflammatory process. At the same time, the more the activity of the various tissues is studied, the more fully it is seen that many cells retain what may be termed reminiscences of an earlier and more embryonic condition in which their functions were varied and less specialised. There is an inherent probability that the endothelial cells can react directly to stimuli, and that they are capable of idiopathic contraction and expansion on appropriate stimuli. We have seen that these cells are capable of taking up microbes, and thus obviously exhibit an independent activity similar to that observed in the aniceba or the wandering phagocyte. If these cells, then, are capable of throwing out pseudopodia, and thus of enclosing non- Digitized by Microsoft® cH.xx PAET PLAYED BY NERVOUS SYSTEM 167 motile bacteria, are they not capable of contracting and expanding, as a whole, according to the stimulus of altered environment ? As a matter of fact, such con- tractility of the endothelial walls of the capillaries has been demonstrated by Klebs (172) and Severini (173). I cannot but conclude, then, that at least the endothelium of the capillaries is to some extent self-regulative or neuro-muscular. It is quite possible that the muscular coats of the smaller arteries are likewise capable of self- regulation, and respond directly to stimuli. In their studies on the sympathetic innervation of the rabbit's ear. Dr. and Miss Meltzer (174) have demonstrated that after section of all the sympathetic fibres to the ear, the resultant hyperfemia disappears in some days, the vessels contracting, and this before any signs of nerve-regeneration can be detected. In other words, the arteries regain their tonicity without the aid of extrinsic nervous influence. That inflammatory dilatation of the vessels differs from simple vasomotor dilatation they demonstrate by the action of adrenalin : this is followed by rapid contraction in the latter condition, but is without effect in the former. The continuance of pulsation in the veins of the bat's wing when the nerves have been cut through, suggests either that the muscle of the walls has independent action or the existence of local ganglionic centres. There is, indeed, something characteristic about the inflammatory dilatation of vessels — something not observed in other conditions — in active arterial hyper- £emia or in venous obstruction. As Samuel (131) points out, if intense venous obstruction of the rabbit's ear be produced, the larger vessels are seen greatly engorged ; but puncture of the skin outside the visible vessels, or even of the ear with a fine needle in such a position, is not followed by the escape of even a drop of blood — Digitized by Microsoft® 168 INFLAMMATION pt. n the capillaries remaining contracted. Puncture outside the visible vessels in the inflamed ear and the outpouring of blood is quite extensive. There is, in short, an active dilatation of the capillaries ; indeed, contrary to the usual teaching, I am inclined to the belief that the hypersemia of inflammation is not a true, active, or arterial hyper- jemia ; still less is it a passive or venous hypersemia ; it is, I hold, sui generis, and best described as a capillary hypercBmia. This view — that the vascular phenomena of inflam- mation can occur independently of the central nervous system and of the peripheral nerves — does not imply that the nervous system, central and peripheral, is without its influence upon the process ; far from it. We have evidence, in the first place, that the state of the vascular walls is modified after destruction or sever- ance of the nerves. I do not here refer only to the consequent alterations in calibre of the vessels, but also to the changes in other properties. Thus Gergens (l75), and to a less extent Eutimeyer (l76), noticed that after destruction of the spinal cord the blood- vessels of the frog permit a larger quantity of fluid, and even particles of granular colouring matter, to permeate them. In the second place, we have evidence that the central nervous system exercises some direct influence upon the inflammatory process. From Cohnheim onwards it has been a matter of common observation that when all the nerves of a part have been severed, the stages of the process succeed each other with greater rapidity. It may be that the modified state of the capillary walls, noted in the preceding paragraph, is capable of account- ing for this fact, and that, in the absence of central influences, dilatation of the vessels and exudation of fluid lead to the cardinal symptoms of redness and Digitized by Microsoft® CH. XX PAET PLAYED BY NEEVOUS SYSTEM 169 swelling, with associated changes iu the tissue, at an earlier period. Of the part played by the different sets of nerves the external ear of the rabbit again furnishes an excellent study. This part has a double nerve-supply through the auriculars (major and minor) from the cervical plexus and the sympathetic branches from the superior cervical ganglion : stimulation of the former leads to dilatation of the ear vessels (vaso- dilator action), of the latter to contraction of the same (vaso-coustrictor). If, as shown by Samuel (177), the sympathetics be divided on the one side, and the auricular branches upon the other, the ear vessels of the former side become widely dilated (unimpeded action of vaso-dilators), and those of the latter markedly constricted. Under these conditions, if both ears be subjected to the action of water warmed to 54° C. there is a characteristic difference in their reaction. In the organ deprived of sympathetic influence the congestion and hypersemia become yet more pro- nounced : an acute inflammation sets in whicl) proceeds rapidly to recovery. In the opposite ear, with its con- stricted vessels, no hyperfemia is set up ; but there is stasis, and gangrene may supervene. These results have been confirmed by Eoger (178), who, taking a rabbit and dividing the sympathetic on one side, and then inoculating both ears with like quantities of a culture of the strepto- coccus of erysipelas, found that the erysipelatous process manifested itself much more promptly upon the paralysed side, and came to an end at an earlier date. The reverse was the case when the auriculars of the one side had been divided : here the process was of slower develop- ment than on the intact side, and of slower course, resulting in mutilation of the organ. Further confirma- tion is afforded by the researches of Meltzer and Meltzer (174). Digitized by Microsoft® 170 INFLAMMATION pr. n The inference to be drawn from these observations is that section of all the nerves passing to the rabbit's ear permits the inflammatory process to run a more rapid course ; section of the sympathetics (vaso-constrictors) alone has the same effect ; while the uncontrolled action of the sympathetics after section of the auriculars (vaso- dilators) hinders or prevents the manifestation of the ordinary processes of inflammation, and by preventing the destruction or removal of irritant matter favours necrosis of the tissues. We have yet to learn whether these results are capable of a general application, and to discover how far they are borne out by clinical observa- tions on diverse cases of localised paralysis. So far as they go they afford direct evidence of the power of the central nerv^ous system to modify the course of the inflammatory process, while they demonstrate admirably how potent an auxiliary is the dilatation of the vessels in the inflammatory process. Other evidence that the state of the nerve-supply of a region influences the manifestation of inflammation is afforded in sundry neuropathies. In all of these, in the present state of our knowledge, it is difficult to trace out the nervous factors associated with the lesions to which I refer. Our knowledge of the respective influences of trophic and vasomotor nerves is far too limited to permit us to say more than that a relation exists between the condition of the nerve-supply of the affected area and the inflammatory lesions there observable ; that in a certain number of cases inflammation affecting the area supplied by one branch of a nerve may have associated with it definite inflammatory disturbances in the areas supplied by other branches of the same nerve, and that, similarly, when inflammation affects a viscus, inflammatory phenomena may be sympathetically developed in regions innervated from the same area in the brain or spinal cord. I have already Digitized by Microsoft® cH.xx PAET PLAYED BY NEEVOVS SYSTEM 171 given examples ia support of the first statement : the familiar redness, swelling, heat, and pain of the side of the face which may accompany toothache is an example in support of the second. Head and Campbell's thorough studies upon Herpes zoster (179) show that lesions affecting the nerve centres— in this case the posterior root-ganglia — may be the main factor in the development of an intense inflammatory process in the areas governed by those centres — a process so far unassociated with the presence of bacteria, although the appearances suggest infection. Another example is to be found in the acute nephritis which at times rapidly follows the passage of a catheter or the impaction of a stone in the urethra. It is not unlikely that many of these sympathetic inflamma- tions are not direct, but secondary. Thus, the first noticeable symptom of catheter fever is suppression of the urine. Such suppression might be brought about either by refiex contraction of the renal arteries, or, contrari- wise, by reflex great dilatation and congestion of the vessels of the kidneys. If it be caused by the former, then the nephritis can only be regarded as secondary, and as due to the injury done to the organ by the stoppage of its blood-supply for some little time. Undoubtedly in many cases of catheter fever the nephritis is infective, but in some the condition supervenes so rapidly that it is difficult to believe that we have to deal with an ascending infection. When there is infection it develops in such a way that we are led to see that the altered condition of the organ under various influences has favoured the inflammatory process. From the multitude of the factors involved, these examples, taken separately, afford at most only a great probability that the nervous system can directly originate inflammatory changes. There is, however, the clearest proof that the nervous system does possess this power. Digitized by Microsoft® 172 INFLAMMATION pt. n and this is afforded by the results of certain observations upon hypnotic effects. In some persons susceptible to hypnotic suggestion, the suggestion that a red-hot substance has been placed upon the hand will, in the course of a few minutes, lead to great reddening of the part supposed to have been burned, and this reddening may be followed by great local exudation and swelling — in fact, by all the symptoms of acute inflammation, save this, that the exudation is simply serous, not passing on to anything approaching pus formation, i.e. the migration of leucocytes would seem to be wanting. Here, then, actual inflammatory reaction follows supposed injury. Characteristically there is a tendency for the lesion to be bilateral, " reflected " upon the corresponding region of the other side of the body. It is uunecessary to do more than point out the light that this intervention of the central nervous system throws upon the subject of counter-irritation, and upon the modifications of the course of inflammations brought about by idiosyncrasy of the individual. From what has been said in the preceding paragraphs it follows that : — 1. Acute inflammation in all its stages, may proceed regularly in the absence of all centrifugal nervous influences. 2. The vessels of an injured area are capable of reacting apart from central influences ; it may be either directly, or under the control of a peripheral system of nerve-cells. 3. The central nervous system is capable of modifying the process of inflammation. It would appear that when the vaso-dilators alone are called into action the successive stages of the process are accelerated. When the vaso-constrictors alone are acting the process is retarded. Digitized by Microsoft® cH.xx PAET PLAYED BY NEEVOUS SYSTEM 173 4. Centrifugal impulses alone, apart from any local injury, may originate a succession of phenomena of inflammation in a part. 5. Hence, in all probability, a liervous and central origin must be ascribed to some, at least, of the sympathetic inflammations seen to occur in areas supplied by the other branches of a nerve supplying a part primarily inflamed ; and again in areas supplied from the same region of the brain or cord as the inflamed organ. Digitized by Microsoft® v.— THE CELLS OF THE TISSUES CHAPTER XXI DEGENERATIVE CHANGES As a consequence of irritation two opposed processes may be manifested in the cells of the affected area, — changes leading to impairment and death, and changes leading to overgrowth and proliferation ; degeneration and regeneration. Either of these two processes may, it is true, be wholly wanting. In very acute suppurative disturbances, destruction of tissue-cells, and the steps leading to destruction may be the only recognisable changes. Again, in the first stage of most injuries, whether of mechanical, chemical, or bacterial nature, degenerative changes are wont to take the lead. On the other hand, there are irritants so mild that little or no cell-destruc- tion results from their action ; an extreme example of this category of inflammations is seen in those epithelial overgrowths commonly known as " corns," due, as Sir James Paget pointed out in his lectures, to intermittent pressure, and irritation of moderate intensity.^ Other ^ It may very well be that this is not an extreme example. Certain neoplasms, or tumours proper, not improbably develop as a conse- quence of some irritation having an intensity just sufficient to induce 174 Digitized by Microsoft® CH. XXI DEGENERATIVE PROCESSES 175 examples are to be found in the " catarrhal " inflamma- tions, in which there is marked initial overgrowth and proliferation of the cells of mucous membranes ; and in tuberculosis, again, in which characteristically the earliest effects upon the pre-existing cells, produced by the presence and growth of the tubercle bacilli, are those of enlargement and multiplication — necrotic changes, as a rule, only appearing at a much later stage. Once more, in the later healing stages of injuries, cell-proliferation may be in the field alone. Nevertheless, in a very great number, if not in the majority, of inflammations, the two processes may be found occurring together — destruction and degeneration being in evidence at the focus of irritation, and growth and proliferation towards the boundary zone, where the irritant is acting in a less concentrated form. Although the two processes are thus so frequently associated, it will be well, for the orderly review of our subject, to consider them separately. Degenerative Changes. — Death of the pre-existing cells as an immediate consequence of injury cannot be regarded as one of the phenomena of the inflammatory process. Immediate death of the cells may be a result of injury, and the disintegration of the dead cells may in itself lead the way to all the symptoms of inflammation. cell-proliferation, and continued for a time sufficiently long to impress upon the cells of the affected tissues the habit of rapid multiplication. There is evidence both in animal and vegetable pathology favouring this relationship between inflammation and neoplastic growth. The objection may be raised, with considerable force, that substances which lead to cell- proliferation are stimuli and not irritants, and that a line should be drawn between inflammation proper and overgrowth the result of irrita- tion. I, for one, would willingly make this difference, but while it is easy to draw the line in certain well-marked examples, in others, as I shall proceed to show, cellular proliferation is so essential a part of the whole inflammatory process that the division becomes impossible. Digitized by Microsoft® 176 INFLAMMATION pt. n But cessation of action is not reaction, nor is failure response, and throughout this study inflammation has been considered as the reaction following injury, and the response to it. Thus immediate death of tissue-cells is resultant and not reactive, and may be eliminated from the category of the essential phenomena of inflammation. The same is to some extent true of cell-degeneration, but not entirely. While it is impossible now to accept Virchow's view, that inflammation is essentially a process characterised by increased nutritive changes in the cells of the tissues (180), it remains most probable that in very many cases irritation induces increased, even if perverted, activity of certain orders of cells. The pro- liferation, swelling, and more or less rapid degeneration of these cells cannot be wholly ascribed to the toxic influence of the irritant, but must in part be regarded as a result of over-stimulation and overwork. This is most noticeable in connexion with catarrhal and paren- chymatous inflammations. In parenchymatous nephritis, for example, such as that set up by cantharidin or infection, the cells especially affected are those whose functions are especially excretory ; and their degeneration would appear to be intimately related to the performance of their functions. Such degeneration, preceded or accompanied, as it so frequently is, by excessive prolifera- tion, may truly be regarded as reactive, and not as wholly and primarily destructive. Of the degenerations which affect the tissue-cells (and often at the same time the leucocytes) in inflammation there are many varieties ; in fact, according to the nature of the irritant, one, or other, or all the degenerations affecting the tissues in different pathological conditions may manifest themselves, save, perhaps, simple atrophy and pigmental degeneration (as apart from pigmental infiltration). Most commonly recognised are cloudy Digitized by Microsoft® OH. XXI DEGENEEATIVE PROCESSES 177 and fatty changes, but mucoid and hydropic changes are far more frequent than is generally noted. Even so specialised a change as amyloid degeneration has been observed occurring locally in chronic inflammations — as, for example, in gummas ; while in these same chronic lesions hyaline degeneration in the vessel-walls is very frequent. There is a further form of degeneration met with in inflammatory disturbances which deserves more recogni- tion than it has generally received. This is what may be termed reversionary metamorphosis. To speak of it as reversionary degeneration is, perhaps, a misnomer, although, if the irritation be continued, the modified cells undergo atrophy and destruction. It is not seen in acute inflammations, but in more chronic cases. As I have pointed out elsewhere, functional activity and active growth and multiplication of the cells of the organism are largely incompatible. The performance of function necessitates katabolism and breaking down ; growth demands a building-up and increase of the cellular bioplasm. Thus, in the course of active cell- multiplication, the individual units lose, to a certain extent, the finely differential histological features associ- ated with the performance of special function, and revert to a simpler, more embryonic type. All inflammatory new growth, when active, presents, indeed, a reversionary character, the cells assuming appearances resembling those seen in the process of fcetal development. Even in the simplest of all tissues, namely, white fibrous connective tissue, this is to be observed. But, in some instances, it is peculiarly well marked. Muscle-fibres, for example, are developed from sarcoblasts — large cells, without a sign of striation but with abundant cytoplasm, tending to become multinucleated. In subacute inflam- mations affecting a muscle, the striation disappears, the N Digitized by Microsoft® 178 INFLAMMATION pt. n nuclei multiply, and, from the common multinucleated mass, there may be budded off or separated, isolated cells resembling hyaline leucocytes with abundant cytoplasm ; resembling, in fact, the embryonic sarcoblasts. The embryonic liver shows no differentiation between liver-cells and bile-duct; both are developed from in- different strands of cells. In the process of development those destined to be liver-cells enlarge, become polygonal, and gain abundant cytoplasm; those destined to become bile-ducts remain small, multiply, and become arranged as an epithelium. Now, in chronic interstitial hepatitis (portal cirrhosis) of the progressive type, we at times surely recognise at the outer border of the affected lobules that the liver-cells become smaller and smaller. Their nuclei also are small, and they have little surround- ing cytoplasm ; they form into little worm-like strands of cells isolated by the newly formed connective tissue; here and there such strands can be followed in direct continuity with the more normal liver-cells of the lobule. These are not true bile-ducts, as they are sometimes mistakenly called : the cells are irregularly arranged and do not form a true epithelium ; they are more of a reversion to the indifferent stage.^ All these degenerations are inevitably associated with disturbances of the functions of the affected cells, and lead to their death if the irritation . which has induced them be continued. But death is not the final stage to be considered. The ultimate fate of the necrosed cells varies according to the situation of the inflamed area, the intensity of the irritation, and the ' While these appearances can be made out in progressive cirrhosis, it should be noted that, in cirrhotic livers showing reactive hypertrophy, another condition giving somewhat the same general appearance is to be detected, namely, active budding and new formation of liver parenchyma proceeding from the bile-ducts (181). This is a process of another order, one of ascent, not of descent. Digitized by Microsoft® CH. XXI DEGENERATIVE PEOCESSES 179 specific character of the irritant. From a free surface the dead material may be freely cast off. In acute suppurative inflammations, whether superficial or deep and, in general, wherever there is an abundant deter- mination of leucocytes, there obtains a digestion and solution of the necrosed cells ; and, as I have already pointed out, this is associated with the liberation of many ferments, the development of peptones, albumoses, fatty acids, and other bodies, and is brought about largely through the extracellular action of the leucocytes and processes of autolysis. When there is a large area of cell-destruction, with well-developed encystment and limitation of necrosis by granulation-tissue, the solution of the dead material and subsequent absorption may be incomplete, and a fatty debris left behind, which may eventually become infiltrated with lime salts (calcareous infiltration, in the production of which, as Klotz (134) has recently demonstrated, the conversion of fatty acids into soluble soaps plays an important part). In tuber- culosis, despite the presence of many leucocytes in the immediate vicinity, the dead material of the centre of the tubercle undergoes very little absorption, but remains as an inspissated, cheesy, and, later, calcareous mass. In syphilis, on the other hand, in large gummas, while there is similar death of the central cells and absence of removal, fatty metamorphosis does not occur nearly to the same extent, nor is there the same tendency towards calcification. Lastly, although very little is known about the subject, it must be pointed out that along with the tissue-cells the intercellular matrix undergoes modifica- tions or degenerative changes during inflammation. Among these, in all probability, is to be classed an increase in the amount of intercellular mucin, a mucoid degeneration. The inflammatory exudate is in many Digitized by Microsoft® 180 INFLAMMATION pt. n cases rich in mucin, and although our knowledge of the changes in the matrix is scanty, the fact that the tissue- cells in general show little evidence of storage of mucoid or mucinogenous material, renders it probable that what mucin is formed is either excreted or elaborated between the cells. Connective-tissue fibrils, as part of the matrix, become swollen and fused into translucent bands or masses, in which the individual fibrillse are no longer distin- guishable : in acute inflammation the next stage is the dissolution and disappearance of this collagenous matter. In chronic disturbances they are especially prone to hyaline change. Digitized by Microsoft® CHAPTER XXII REGENERATIVE CHANGES In the lower animals, as we know, injury and actual removal even of a large portion of the body may be followed by the complete reproduction of the lost part. In man, however, this reproduction of lost tissue is reduced to its lowest point ; the higher the tissue the less, and the less perfect, the reproduction. Speaking generally, the tissues which show tlie greatest potentiality for reproduction are the least highly organised — those composed of similar units. The " connective tissue " — the lowest and most widely distributed — retains the largest powers of proliferation and hyperplasia. In ordinary inflammation, hypertrophy and hyper- plasia ^ of the connective-tissue cells are absent at the focus ■ of irritation. Here degeneration is predominant. It is in the peripheral zone, away from the maximum concentration of the irritant, that (as shown in case after case of Leber's long series of studies upon injury to the cornea) the connective-tissue cells show signs of enlarge- ment and proliferation, that they become more swollen and prominent, send out large processes, and may exhibit signs of active mitosis. Regarding the mode of multi- ^ By hypertropliy in the strict pathological sense is indicated increase in size of the individual elements of a tissue, by hyperplasia increase in the number of these elements. 181 Digitized by Microsoft® 182 INFLAMMATION ct. n plication of these cells, there is now a general consensus of opinion that multiplication by direct division (ami- tosis) is apt to show itself first even within a few hours of the infiiction of injury. In an incised wound, or in the cornea, an occasional mitosis has been observed as early as the twelfth hour, but in general it is only by the middle of the second day that indirect cell division is easily recognisable. It may be urged that this peri- pheral change is not inflammatory, but associated; yet, as I have already hinted, the signs of cellular regenera- tion may manifest themselves at so early a stage that it is impossible to disconnect them from- the process of inflammation. This has been brought out with emphasis in Eanvier's interesting series of studies on irritation of the peritoneum by weak solutions of caustic substances, to which reference has already been made (p. 72). With abundant fibrinous exudate, engorgement of the vessels of the serous coat, presence of polymorphonuclear cells, and other signs of active inflammation, there is active direct, followed by mitotic division of the endothelial cells, some of which become enormous — 100 /x and more in diameter. These cells send out processes, and take, some of them, an active part in the formation of ad- hesions. This is agreed, though the exact part is still a matter of controversy, whether (von Brunn (64)) they merely afford the endothelial layer covering the newly organised adhesions, or actually in part develop into fibroblasts. Here the main point is that during active inflammation cells of endothelial type are often to be seen in a state of active enlargement and multiplication. As Baumgarten (182) showed in his studies upon the development of tubercles, in the irritation set up by the growth of the B. tuberculosis in the tissue, a like over- growth with proliferation of the fixed cells occurs in the immediate neighbourhood of the bacilli without any Digitized by Microsoft® CH. xxiT REGENEEATIVE CHANGES 183 primary evidence of cell- degeneration. It is true that the researches of Barrel (81) have thrown doubt upon Baumgarten's observations, but they confirm the earlier researches so far as regards the mitosis of pre-existing cells, and the absence of degeneration of these in the earlier stages of the tuberculous growth. Borrel would regard all the large epithelioid cells of the tubercle as modified leucocytes. If we assume, as I think we must, that cells of the hyaline mononuclear type have a common origin, whether passing to the part from the blood or developing from pre-existing cells of the part — that hyaline mononuclear cells are derived from endothelial cells in the main — we then harmonise, or find a via media between, these opposing views. It deserves mention that Virchow's teaching that cells may undergo growth as a consequence of the inflammatory reaction, was vigorously opposed by Carl Weigert (183), according to whom cell growth and formative, as distin- guished from functional processes, were an intrinsic inherent property of living matter, a property that could not be stimulated by chemical and other influences acting from without, though it could be hindered in its mani- festations by mechanical influences such as the pressure of surrounding cells. What Yirchow had adduced as examples of cell growth he regarded as evidences of cell degeneration. "Weigert's views have exercised a profound influence upon the pathology of the past generation. They do not, however, express the whole truth and are untenable. He neglected to take into account in his reasoning on this matter the possibility that increased functional activity on the part of the cell, initiated from without, might under certain conditions not merely result in heightened katabolism, but that in this process of katabolism the products of dissociation of the cell sub- stance might attract other matter to the cell, and so Digitized by Microsoft® 184 INFLAMMATION pt. n favour a coincident and even greater assimilation, leading to increase in the amount of cell substance. Certain it is that of late abundant instances liave been brought together by Levin (184) and others which can only be interpreted on the view that a certain grade of stimulation or irritation favours cell growth, and a higher grade cell disintegration — the position, I may add, upheld in the first edition of this study. Physiologists are now afford- ing abundant instances to the point, demonstrating, for example, that the internal secretion of the thyroid directly stimulate growth, and that the growth of the mammary glands during pregnancy is not of nervous origin, or in any way connected with nervous control, but is due directly to the influence of substances diffused into the maternal blood from the growing foetus during pregnancy. Pro- fessor Starling (185) in describing his series of experi- ments affords a useful resume of cognate examples. The difficulty of determining the origin of the growing cells in inflammation has formed the greatest trial of the pathologist throughout an entire generation, and yet longer ; nor can we now assert without chance of dispute what cells are mainly concerned in the formation of new tissue. When we examine newly formed granulation- tissue we can distinguish cells of more than one type — (1) small round cells with polylobular and fragmented nuclei, (2) other cells containing oxyphil granules, (3) larger cells with a single nucleus and a relatively large quantity of protoplasm, and again (4) cells of varying but generally of large size, varying in shape, but on the whole having the appearance of spindle-cells with single oval nucleus and abundant protoplasm. These can be made out easily. The first two forms of cells are clearlj' hasmatogenous leucocytes. Further study of their fate shows that they disappear; tliey play no further part in the organisation Digitized by Microsoft® EEGENERATIVE CHANGES 185 of the tissue save that, as is well shown by Scheltema and Nikiforoff (186), many of them are absorbed by the growing connective-tissue cells, and thus would seem to aid in their nutrition. The last form likewise presents, as such, no difficulties. These are fibroblasts— cells in the process of growth into connective tissue. But what is their relationship to the previous form, — to the round mouonucleated cells with fairly abundant protoplasm,- — what are these last, and what, in short, is the origin of Fig. 18, — Spindlc-cells and developing connective tissue in an air-sac of a piece of haiiiened lung introduced into the peritoneal cavity of a guinea-pig, showing well early stages of development of the fibroblast (seventh day). The cells lie in a net- work of fibrin. — Marchand. the fibroblasts, — is it fronr leucocytes or from pre-existing connective- tissue cells ? Upon this most difficult ques- tion more ingenuity and more research have been expended than upon any other part of this well-worked field of inflammation. There can be no doubt now that a large proportion of the fibroblasts in granulation-tissue are developed from pre-existing connective -tissue cells. The general con- sensus of recent researches leads decidedly in this direc- tion ; and it is from the laboratory of Ziegler, who by his classical observations led pathologists for some years Digitized by Microsoft® 186 INFLAMMATION pt. n to hold the contrary view, that the studies have emanated which most conclusively show the part played by the con- nective tissue; the researches of Krafft (18*7), Podwys- sozki (188), Coen (189), Fischer (190), and Nikiforoff, confirmed and strengthened by the researches of Arnold (191), Marchand (192), Eeinke (193), and Sherrington and Ballance (194), and the more recent researches of von Brunu, Maximow, Monckeberg, and a host of other workers, all bring forward evidence in one direction. It is the clearly recognisable pre-existing cells of the tissue — connective, endothelial, and epithelial — which show most constantly the signs of nuclear division : every stage of enlargement, mitosis, and cell-division can be made out in them. Even if we did not possess the information afforded by nuclear changes, the fact that new tissue is always developed in, the imviediate neighbourhood of pre- existing tissue would in itself point strongly to this same conclusion. We may rest assured of this much. But can we advance farther, and state that all newly formed con- nective-tissue cells originate from the pre-existing cells of the tissue, and that none of them are derived from wandering cells ? In the present state of our knowledge the answer to this question must be an unhesitating " No." We have evidence, in the first place, that cells of the hyaline mononuclear type show all transitions from round- or spindle-shaped cells to definite fibroblasts in the process of forming connective - tissue fibrillae (Maximow and others). Metchnikoff has followed day by day the transition from the interstitial wandering cell of this type into the connective-tissue cell ; this in the tadpole's tail. Evidence was brought forward {vide p. 75 et seq.) that these hyaline mononuclear cells are histogenous, developed from pre-existing tissue, more particularly from connective tissue and endothelium. Digitized by Microsoft® OH. XXII REGENERATIVE CHANGES 187 The proliferated and " embryonic " endothelial cells of vessels have been observed in the process of migration into the surrounding area ; in short, proliferating tissue- cells in an area of inflammation, in the process of forming new cells, revert to a simpler, more embryonic type ; they become round cells of the order of leucocytes ; they exhibit pliagocytic properties ; they give off pseudopodia ; they are capable of movement and translation ; they become, for the time, wandering cells. And other cells of the same order, the heematogenous mononuclear leucocytes, which, as has been pointed out, are presumably of like endothelial — i.e. connective-tissue — origin, when they migrate into an area of inflammation have like properties. There are, in short, histogenous wandering cells, and, once this is admitted, active controversy, save on matters of detail, comes to an end. It may be stated that the fate of these histogenous wandering cells is a matter of environment, of relative position ; if they remain in the neighbourhood of the vessels of the inflammatory zone, they are able to develop into fibro- blasts, and give origin to new tissue ; if, being of endothelial origin, they find themselves lying over a surface they form endothelium ; if they wander farther afield into the area of inflammatory necrosis they con- tinue to comport themselves as wandering cells, at most acting as phagocytes, and undergoing eventual dissolution, or, more rarely, finding their way back into the vascular system. Thus it is that, as already stated, new tissue is laid down always in the immediate neighbourhood of pre-existing tissue ; that is to say, in the neighbourhood of blood-vessels and of adequate nutrition. What is more debatable is whether cells of the lymphocyte type under any conditions give origin to new connective tissue. Our own opinion is that they do not, and in this we have the support of Schridde's Digitized by Microsoft® 188 INFLAMMATION pt. ii observations that while these cells may become elongated and spindle-shaped, resembling fibroblasts, they neverthe- less retain a differential granulation, and cannot, therefore, be regarded as fibroblasts proper. But there are those who uphold strongly the possibility of such a conversion, notably Maximow. We have to admit that in subacute and chronic inflammation, no satisfactory determination has been made of the fate of the abundant interstitial small round cells of the lymphocyte, or again of the plasma-cell type, or of the stages by which these cellular accumulations become replaced by fibrous connective tissue. This, I believe, expresses the outcome of the more recent studies upon the matter, and to epitomise we may say: — 1. Two series of changes may occur in the cells of an inflamed tissue, which may be included under the terms degeneration and regeneration respectively. 2. The extent to which one or other of these series of changes predominates varies with the nature and intensity of the irritant. 3. Degeneration and death of the tissue-cells may be a direct and immediate result of the presence of the irritant, and then can scarcely be regarded as essential phenomena of inflammation. Or they may be of more gradual onset, associated with evidence of over-stimulation and increased activity of the cells. 4. Fatty, cloudy, hydropic, and mucoid are the most frequent forms of degeneration affecting the tissue-cells in acute inflammation ; hyaline in chronic ; other forms are rare. 5. The ultimate fate of the necrosed cells varies as the situation, intensity of irritant, and specific character of the irritant. 6. Cell -proliferation is so constant an accompani- Digitized by Microsoft® OH. XXII EEGENEEATIVE CHANGES 189 ment of certain forms of inflammation that it is impossible to regard this as an adjunct and not as an essential part of the process. 7. The tissues which show the greatest potentiality for reproduction in consequence of inflammation are those which are least highly organised. 8. The origin of fibroblasts and new connective-tissue cells is still in some details a matter of controversy, but this much would seem to be clearly demonstrated : That while the larger proportion of the fibroblasts are derived from the pre-existing counective-tissue cells of the part, others may have originated from histogenous wandering cells that have migrated from some distance. Free hematogenous leucocytes (polymorphonuclear and eosino- phil) do not give rise to new tissue ; whether lymphocytes can do so is still under debate. The practical identity between young cells of hyaline mononuclear type and newly proliferated connective-tissue and endothelial cells makes it impossible to determine with precision the point of origin of any individual cell by histological methods alone. Digitized by Microsoft® CHAPTEE XXIII ON FIBROUS HYPERPLASIA AND ITS RELATIONSHIP TO INFLAMMATION The succession of changes from embryonic cells to fully formed tissue can best be studied in cases where there has been a relatively large area of destruction — as, for example, after severe burns, or excision of organs or large portions of organs ; or, again, where inflammation has been of a chronic character. Granulation - tissue can be studied well in the granulating wound, a form of inflammation regarding which, as yet, we have said very little, frequent though it is in surgical experience. When, through injury, the skin or superficial protective layer of a part is removed or destroyed, and the underlying tissue exposed, the first stages are those already described, namely, of dilatation of the vessels in the immediate neighbourhood of the injury, exudation of fluid, migration of leucocytes, and so forth. The extent of the migration depends largely upon whether the wound has become infected or no ; but even where infection from without has been prevented, in every case where deeper layers are exposed, and not brought together, there is a certain amount of diapedesis, apparently induced by the presence of products of cell- ancl tissue-destruction. Where superficial infection takes place, the migration of leucocytes is much more abundant, 190 Digitized by Microsoft® CH. xxin FIBEOUS HYPEEPLASIA 191 and in place of a thin layer of exudate tending to undergo coagulation and form a scab, there is a surface accumulation of pus, without coagulation. With the Fig. ]9. — Granulation - tissue seen from the deeper toward the upper surface. 1. Spindle-cells, most abundant in deeper portions, where they are also becoming swollen ; 2. Polymorphonuclear leucocytes, most abundant towards outer surface ; 3. Lymphocytes ; 4. Capillaries. — After Ribbert. present aseptic methods of treating wounds we are not accustomed to see now any abundant development of pus over an exposed wound. Formerly it was different, and a distinction was made between laudable and foul Digitized by Microsoft® 192 INFLAMMATION pt. ii pus ; the former being bland, creamy, and of sweetish odour ; the latter discoloured and foul through the abundance of putrefactive microbes, and accompanied by progressive breaking down of the tissue bordering on the wound. " Laudable pus " seems to us to-day a misnomer. With modern methods pus is regarded as matter out of place and far from praiseworthy. And yet more than one recent observer has shown, by direct experiment, that pus of this nature on an exposed surface has properties which we cannot describe as other than laudable. It has been shown to act as a barrier. Add to such pus covering a granulating wound a suspension of some known pathogenic microbe, and, unless these be added in excess, they do not set up general infection ; they are not to be detected in the underlying tissue. Pus is definitely bactericidal. It would seem that the underlying, newly formed granulation-tissue partakes also in these bactericidal properties (Jiirgenllinas (195)). Beneath this surface layer new tissue begins to form. The process of growth is seen to originate in the immediate neighbourhood of, if not in direct connexion with, the layer of dilated capillaries immediately border- ing upon the wound. As already described, these project outwards towards the exposed surface, and from them are developed or projected new capillary loops. As these form there is a rather remarkable clearing in their immediate neighbourhood. The abundant leucocytes and fibrin (if present) or cell-debris disappear, and whether by phagocytosis, autolysis, and dissolution, or by re-migration of the still active leucocytes into the vessels, the area immediately around the capillary loop becomes relatively free. From the first series of capillary loops other capillaries are projected, until the whole surface of the tissue, when cleansed, if necessary, of overlying pus, is seen to be covered with a finely granular or coarsely Digitized by Microsoft® CH. xxiir FIBEOUS HYPEEPLASIA 193 velvety, reddened, injected layer. This is granulation- tissue. Beattie and Dixon (196) describe a primary capillary net-work projected into the overlying fibrin, which may be well developed in an incised wound from twenty-four to thirty-six hours after infliction, around which the clearing away of cellular exudate is well pronounced. This they state is a temporary granulation tissue. This branching thin-walled capillary network tends to disappear, and in from thirty-six to forty-eight hours a second more regular set of new capillaries makes its way upwards from the deeper parts of the wound, better supported than the delicate primary set. The new fibroblasts become arranged at right angles to the axes of this new series of capillaries. If healthy granulation-tissue be examined, the process of growth is seen to originate in the immediate neighbour- hood of, if not in direct connexion with, the dilated new capillaries. It is around these vessels, formed of little more than a single layer of cells, that the fusiform fibro- blasts are in greatest abundance. At a later stage, in regions more remote from the advancing margin of the granulations, the fibroblasts have a more general disti'ibu- tion in the intercapillary spaces, and are more elongated ; around them may be seen the earliest wavy fibres of white connective tissue. These are essentially of cellular origin — as much so as is the substance of striated muscle-fibres. The elongated fibroblasts not only break or extend at their poles into fine processes, but also along their sides the protoplasm undergoes modification into fine parallel fibrillas. With the continuance of this change the cells become smaller and smaller until little is left but the attenuated nuclei, often so flattened and narrow as to be scarcely recognisable. With increasing age the fibrillar substance contracts; certainly the newly Digitized by Microsoft® 194 INFLAMMATION pt. n formed cicatricial tissue dirainishes greatly in volume, and with this diminution the previous great vascularity of the part disappears ; the capillaries shrink until the majority become completely occluded. Thus in place of the abundant, soft, and succulent granulation-tissue, rich in cells, blood - vessels, and exuded fluid, there is eventually (in three or four M'eeks), a firm, shrunken anfemic mass of fibrous tissue, with a few flattened nuclei, and rich only in closely pressed bundles of white, semi- transparent fibrils. Mastic Tissue. — In the new tissue there may be a certain number of the coarse fibrils of elastic tissue. The development of these has been somewhat extensively studied of late. The conclusion reached is that their development is governed by cells which so far are not to be distinguished from those forming ordinary connective tissue (197). Fibrosis. — Fibrous hyperplasia may be met with in almost every tissue of the body as a sequence of very diverse morbid conditions. To speak of it in any case as " fibroid degeneration " is a misnomer. The over- growth of any tissue, however lowly, is not a degenera- tion. Fibrous tissue may and often does become the seat of degenerative processes, notably the hyaline'; but that is another matter. To regard every condition of generalised or localised fibroid change of the organs of the body as a chronic " ■ — itis " is equally erroneous ; for, as we shall point out, there are conditions of fibrosis which cannot be regarded as the result of irritation and injury. And even when everything indicates that the fibroid change is of inflammatory origin, the caution must here be given that unless the condition is pro- gressive, it is a source of confusion to term it a chronic " — itis." It is a mistake to term an old-standing case of complete pericardial adhesion " chronic pericarditis " Digitized by Microsoft® CH. XXIII FIBEOUS HYPEEPLASIA 195 unless there are indicatious that the condition is still advancing. The inflammation may have been arrested years previously. Such a state should for clearness be spoken of as " pericardial adhesions " or " old adhesive pericarditis.'' It is interesting to note the opposed tendencies of the two branches of our profession on this subject ; the surgeons strive to restrict the idea of in- flammation to acute pyogenic disturbance, the physicians to extend the idea so as to include all cases of chronic progressive " fibrosis." I will not say that the latter is as untenable a position as the former, for it is a matter of peculiar difficulty and delicacy to state what is and what is not an inflammatory fibrosis ; after all, there is more danger of being tossed about helplessly in the Charybdis of including too little, than there is of striking upon the Scylla of including too much in our idea of inflammation. Here I wish to point out how divergent are the conditions which lead to fibroid hyperplasia, and to show that there is reasonable ground for not classing all forms under the one common heading, even though the resulting appearances may be undistinguishable, and the effects the same. Inflammatory Fibrosis. — Let us, in the first place, consider the conditions that are certainly of inflammatory origin. The study of the various stages in the develop- ment of a tubercle demonstrates that, in man and most mammals, the first result of the lodgment and growth of the tubercle bacillus in the tissues is to stimulate tissue- formation. Only at a later period, with continued action of the products of the bacillus, does tissue- destruction become manifest ; and, even here, in a progressive tuber- culosis of modern intensity, we find that while in the central mass the new tissue is breaking down, at the periphery there is definite formation of new fibrous Digitized by Microsoft® 196 INFLAMMATION pt. ii tissue. It cannot be said that here we have an instance of two processes, of inflammation and repair, going on simultaneously, for, studying a series of cases, we find that so-called repair — the tissue- overgrowth — precedes a so-called inflammatory disturbance — the necrosis and caseation ; the same influence causes both conditions. This newly formed connective tissue is clearly a pro- ductive fibrosis of inflammatory origin. Now let us consider what seems to be a very different condition. Where there is atrophy or destruction of sundry motor centres in the brain or section of the lower part of the cord, or destructive lesions affecting the cells of the ganglia of the posterior nerve-roots, there results degeneration and death of the axons forming certain descending or ascending tracts in the cord ; and the death of the axons is gradually followed by replacement with fibrous tissue of a special type, largely the result of overgrowth of the glial cells and their processes, the specific connective framework of the nervous system. Here there has been no irritant from without circulating from the lymph-channels to the fibres and causing their destruction ; the degeneration and the fibrosis have followed injury' at a distance. Is this " replacement- fibrosis " to be regarded as a form of chronic inflamma- tion ? No exogenous irritant has been at work ; nay, more, the process is so gradual that often none of the ordinary accompaniments of inflammation are to be recognised. Even in the early stages the indications of hypereemia, migration of leucocytes, formation of new capillaries, are often of the slightest. But, on the other hand, what distinction is to be drawn between the process seen here, and the grosser changes which occur in non-infective infarcts ? Where, for instance, a branch of the renal artery becomes plugged by a mass of clot, and — as a consequence of the condition of the renal Digitized by Microsoft® cH. xxm FIBEOUS HYPERPLASIA 197 circulation— the area of kidney tissue served by this branch becomes wholly cut off from its blood-supply and dies, we find that the dead tissue becomes replaced by what is clea^y cicatricial fibrous tissue. In such infarcts we can recognise the whole succession of inflammatory phenomena. The capillaries immediately surrounding the wedge of dead tissue become greatly dilated ; there is abundant migration of leucocytes into the area ; the dead tissues, by their action and by autolysis, become broken down and dissolved, and, coincidentally, the surrounding walls give off new capillary loops into the area. We have, in fact, the formation of granulation- tissue with a resultant fibrous tissue -formation and replacement of the dead by cicatricial tissue which, like cicatricial tissue in general, eventually contracts. Here surely we have an inflammatory process set up by the death of the kidney cells, which, dying, liberate diffusible irritants, initiating a series of changes in connexion with the surrounding vessels. The changes seen in the cord and in the kidney differ in degree only, not in kind. We must thus recognise at least two types of in- flammatory fibrous tissue-development ; the one productive or hyperplastic; the other, as I have termed it, replace- inent-fibrosis. In the latter the amount of new fibrous tissue developed appears to be in proportion to the extent of the destructive process ; in the former, continued irritation leads to an overgrowth not related to previous tissue-destruction. (1) Productive Fibroses. — Among these are to be included various localised fibroses, such as the focal areas of new connective-tissue growth set up by the presence of certain micro-organisms, notably those causing the more chronic types of infective granulomas, as, for example, the tuberculous nodules of the tubercle bacilli ; syphilitic gummas ; the nodules caused by the presence Digitized by Microsoft® 198 INFLAMMATION pt. n of leprosy bacilli ; the extensive tumour-like masses set up in man and cattle by the ray fungus or actinomyces ; the new growths around certain pathogenic blasto- mycetes or yeasts, more particularly studied by Gilchrist (198) and other American observers. Similar tubercle- like nodules may be formed around certain pathogenic moulds (aspergilli) (Boyce (199) and others), and we encounter them also around minute larval nematode worms. Not unlike these are the capsular fibroses, those cases of connective -tissue development forming around the irritant, whether infective or no. Here the zone of tissue -formation is a development of so much new material laid down irrespective of previous tissue- destruction ; the thick capsules forming around chronic abscesses and phthisical cavities ; around impacted bullets, or, as frequently observed in the lungs, around inhaled particles taken into the tissues by the agency of the leucocytes. Here also must be included the fibrous overgrowth due to inflammation of serous surfaces, including in this the fibroid thickening of those surfaces and the develop- ment of organised inflammatory adhesions. The new formation in some of these cases may be most extensive, more particularly in conditions known as chronic hyper- plastic serositis, or as Nicholls (200) has termed it, hyaloserositis ; the liver, spleen, or pleura may be covered by a thick layer of dense, hyaline, almost porcelain-like connective tissue laid down in successive layers which may be a centimetre or more in thickness. With these are to be included the general productive fibroses of inflammatory origin affecting the substance of different organs. Such, for example, is the chronic interstitial pneumonia following upon chronic pleurisy, in which bands of fibrous tissue are laid down along Digitized by Microsoft® OH. XXIII FIBROUS HYPERPLASIA 199 the lymphatics passing from the pleural surface. And here also we may include the generalised interstitial fibrosis of so-called chronic parenchymatous diseases, such as we see, for example, in productive parenchymatous nephritis, in which, secondary to the inflammation of the tissue-cells proper of the organ, there is an overgrowth of the fibrous stroma. It is to be noted that some at least of these later cases must be regarded as admixtures of productive and replacement conditions, there being a coincident destruction of the parenchymatous cells. (2) Eeplacevient- Fibroses. — Here we can distinguish certain well-defined types, though all may be termed cicatricial. Wherever we have breach of continuity in a part, there is a tendency for that breach to be filled up by new tissue. In some cases this new tissue is a regeneration of the higher specific cells of the injured organ. In general, however, it may be laid down that the more highly differentiated a tissue, the less is the capacity of its cells to regenerate, so that, more often, it is the lower, humbler connective tissue that repairs the breach. Under this heading, therefore, we place cicatrices of various orders, and include, as already stated, the replacement of dead tissue seen in a simple infarct, where there has been sudden death of the tissues (necrosis), and the replacement-fibrosis seen where tracts degenerate in the spinal cord, and other cases in which fibrosis follows necrobiosis, i.e. slower death of the tissue preceded by atrophy and degeneration. Possibly this is the right place also to include the organisation of thrombi ; that is to say, of masses of coagulated blood within the vessels. When the blood thus coagulates, its cells largely break down, so that the fibrinous products may be regarded as non-living necrotic tissue. While this, in part, undergoes absorption, if it be not infected, a portion at least becomes organised by granulation- Digitized by Microsoft® 200 INFLAMMATION pt. n tissue spreading into it from the vessel wall, and so, eventually, is replaced by a fibroid mass. We may thus classify the forms so far brought forward as follows ; — A. Productive ok Hypekplastic Fibkosis : f focal, 1. Localised , , [capsular. 2. Serous and adhesive 3. Interstitial. [local, [generalised. B. Eeplacement-Fibeosis. 1. Cicatricial. 2. Post-necrotic. 3. Post-atrophic. C. Mixed Fibrosis : both processes being in evidence. Transitional and JVon- inflammatory Fibroses. — This does not, however, exhaust all the conditions of connective- tissue overgrowth occurring in the organs of the body. We have, in addition, fibroid neoplasia and fibromatosis. It is difficult in every case to separate these off sharply from the productive fibrosis of inflammatory origin, for we have a series of what may be termed transitional forms. Typical, encapsulated, fibroid tumours develop without any clear history or indications of previous inflammation. We have here a neoplastic fibrosis or fibromatosis which, for the present at least, we must sharply distinguish from the inflammatory conditions, and that because, as already indicated, we are ignorant of its causation. There is, however, a curious condition known as keloid, especially liable to occur in certain races, as among negroes, and in certain families or individuals Digitized by Microsoft® CH. xxiii FIBEOUS HYPEEPLASIA 201 in whom a very slight irritant, which in ordinary- individuals would lead to no ill effects, is followed by a progressive growth of fibrous tissue. The pressure of a basket carried on the shoulder, or even of a collar button on the neck, has been known to set up this localised but subcutaneous-spreading fibrous overgrowth ; and, indeed, masses several pounds in weight have been so produced. In a case studied by one of my students, Mr. E. Martin (201), a mere scratch by a pin along the arm led to the appearance, in a few days, of a series of small new growths in the line of the scratch. Here, then, irritation originates a new growth that. is wholly out of proportion to the intensity or duration of the irritation. This, however, is not a true fibromatosis, inasmuch as, frequently, the new growth undergoes atrophy and disappears. It is an intermediary condition between the two processes of inflammation and neoplasia. As I have pointed out elsewhere, there is yet another series of cases in which what we may term stimulation rather than irritation — if we can draw a line between the two — is followed by new connective-tissue growth. These cases I can but indicate here. I would only point out that in the ordinary form of arteriosclerosis, for example, fibroid thickening of the intima does not appear to be directly associated with inflammation of this portion of the artery ; everything appears to indicate that it is the media that, undergoing degeneration, first gives way, and that the thickening of the intima and the overgrowth of its connective-tissue cells is wholly a compensatory process. I have suggested that, just as in those who are muscular and accustomed to active exertion, we find that the bone, subject to strain at the origin of the various tendons, shows there a marked over -development and growth into definite ridges, or even into processes, so, where the arterial wall gives Digitized by Microsoft® 202 INFLAMMATION pt. n way, the distending strain to which the well-nourished intimal cells are subjected favours their proliferation and the development, immediately beneath the endothelial surface, of layer upon layer of new cells, until — the area of dilatation being filled up by the new tissue — the calibre of the artery is restored to the normal, and the extra strain or tension upon the intimal cells is removed (202). The recent observations of Jores (203) upon arterio- sclerosis demonstrate that this overgrowth occurs also (he holds, mainly) in the musculo-elastic layer of the intima lying immediately within and against the media. As pointed out recently by my colleague, Dr. C. F. Martin (204), an allied fibrous overgrowth of the intima and media of veins is much more common than is usually imagined. Such Phlebosclerosis affects more particularly veins that are poorly supported, and this even in young adults ; it is unassociated with any obvious signs of progressive inflammation, and must, Martin concludes, be placed in this group of '' strain- fibroses." The overgrowth of fibrous tissue around the veins — in the liver, for example — in cases of prolonged chronic venous congestion (where this is not excessive),^ and that remarkable connective-tissue overgrowth of a part in which there is obstruction to the main lymph-channels which constitutes the common type of elephantiasis, are both, we would suggest, of this same order of new connective-tissue growth, due rather to strain and stimulation than irritation, and so more of a physiological than of a pathological and inflammatory type. In this connexion may be noted certain observations ^ I agree with Eolleston (205) thus far, that advanced and severe passive congestion is not accompanied by fibrosis of the central veins of the liver lobules. I have, however, seen this well marked in cases where there has been a long-continued, slight grade of the condition. Digitized by Microsoft® CH. xxiii FIBEOUS HYPEEPLASIA 203 by Thoma (206). In his wonderfully painstaking series of observations upon arterial changes, he has adduced two cases which he describes as examples of " end- arteritis," but in which the inflammation is not apparent, nor indeed any factor other than altered tension of the arterial walls leading to altered conditions of nutrition. He shows that immediately after birth there is developed a thickening of the intima — a connective-tissue prolifera- tion immediately below the endothelium — of that portion of the aorta lying between the ductus Botalli and the passing off of the umbilical arteries. During later foetal life the umbilical arteries are the largest branches of the aorta ; and, when the circulation through them is arrested, the aorta above is too large for the amount of blood requisite for the abdominal viscera and the lower extremities. The arterial current becomes, therefore, relatively slowed, and presumably, judging by the analogy of what occurs in the adult when large branches of the aorta are ligatured, the aortic blood-pressure is for a time raised. With this slowing and increased pressure there appears a compensatory overgrowth of the intima leading to con- traction of the vessel and its lumeii. Generally speaking when the area of distribution of an artery is diminished, as, for example, when a limb is amputated, the artery shows a similar proliferation of the intima. In both cases the blood remains healthy, and the intima has undergone no injury ; the only recognisable change has been a slowing of the blood-stream, and probably increased blood-pressure ; and as the intima is nourished, not through the vasa vasorum, but directly from the main arterial fluid, it would appear that with the slowing an increased nutrition is brought into action. This is Thoma's explanation : mine differs somewhat in regarding the overgrowth as resulting from increased strain coupled with increased nutrition. I can see no satisfactory Digitized by Microsoft® 204 INFLAMMATION pt. n reason for calling either of these cases an endarteritis. It is quite possible that other cases of thickening of the intimaare due not to irritation, but to increased nutrition with accompanying heightened arterial tension. The difficulty urged by Councilman (207), that high arterial pressure does not invariably lead to overgrowth of the intima, is not, in my opinion, insuperable. It is, I would urge, purely a matter of grade, of the distinction between strain and overstrain. Numerous examples could be adduced in which moderate increase in the work which a tissue is called upon to perform is followed by overgrowth of that tissue : whereas excessive work is followed by rapid exhaustion and atrophy. In this relationship it may be recalled that when the intima of an arteiry is overstretched, as in the development of an aneurismal sac, there is no sign of overgrowth, but rather of the reverse. A most instructive example of this strain hypertrophy of the vessel wall has recently been adduced by Carrel (208) in his brilliant studies upon the transplantation of organs. If a length of an artery, such as one of the carotids, be removed and, with due precautions, be replaced by a length of healthy vein from the same animal, of approximately the same calibre, the circulation may be resumed without clotting, and in the course of a few weeks the vein undergoes a striking hypertrophy of all its coats, the fibrosis of intima and adventitia being most marked. A like overgrowth in the venous wall is noticeable when the central end of an artery is anastomosed to the peripheral end of a vein, e.g. the common carotid to the external jugular (209). It must suffice if here I point out that it is more than probable that certain cases of so-called endarteritis are in no sense of inflammatory origin, or secondary to degener- ative changes. In this connexion it was shown by the late Prof Eoy and myself (210) that when the aorta of Digitized by Microsoft® OH. xxiii FIBEOUS HYPEEPLASIA 205 the dog is suddenly aud greatly constricted, and as a consequence the pressure in the- proximal portion of the vessel greatly increased, the plasma of the blood is forced into the cusps of the aortic valves, aud vesicles of lymph make their appearance on the under surface in that region where fibroid thickening is most frequent in cases of chronic high arterial pressure. And I am inclined to consider that some at least of the cases of chronic endo- carditis, so-called — the cases in which there is a general- ised diffuse thickening of the valve-segments with the non-vascular new fibrous tissue laid down in layers parallel to the surface, the most recent immediately beneath the endothelium — belong to this category of non-inflammatory fibroses. Thus, to express briefly the distinction that we would draw between inflammatory and non-inflammatory fibrous hyperplasia, I would say that where local injury leads to increased nutrition of the connective tissue, with increased functional activity of the cells, the ensuing fibrous hyperplasia is to be regarded as of inflammatory origin ; where, on the other hand, local injury is not recognisable as the primary cause of the cell-growth, the hyperplasia must be held to be non-inflammatory. In passive congestion, obstructed lymph - flow, and the moderate increase in strain consequent upon arterial change, as in the cases cited above, we can so far see no cause for the fibrous hyperplasia beyond altered conditions of imtrition, coupled with increased functional activity (strain) ; there has been no primary lesion in the affected regions inducing the reaction. Such cases must be considered as non-inflammatory. We thus arrive at the following classification of the fibroses : — Digitized by Microsoft® 206 INFLAMMATION FoEMS OF Fibrous Hypeeplasia A. Inflammatory. 1. Productive. 2. Replacement. 3. Mixed. B. Neoplastic. 1. Transitional, of irritative origin (keloid). 2. Neoplastic proper, of unknown origin (true fibroma). C. Functional. 1. Arterial. 2. Venous. 3. Lymphatic. Digitized by Microsoft® YI.— TEMPERATURE CHANGES CHAPTER XXIV ON THE INCREASED TEMPERATURE OF INFLAMED AREAS Very little has of late been added to our knowledge in this division of our subject : what is to be said appears now to be so well established that I need do little more than state the main conclusions. The long controversy that raged before these conclusions were fully accepted, and John Hunter's original views shown to be in the main correct, scarcely comes within the scope of this article. 1. The temperature of superficial regions is raised, it may be several degrees above the normal, by the onset of inflammatory hypereemia. 2. The temperature of internal organs when inflamed may be raised above the normal, but undergoes no material increase beyond that of other unaffected internal organs tested at the same time. 3. The rise above the normal, which is often present, is an indication of the febrile state accompanying the inflammation, and not of locally increased heat-production. It is deserving of note in this connexion that botanists have demonstrated clearly that local injury in the higher plants is followed by a local rise of temperature which can 207 Digitized by MicrosofpS\ i / 1 ' i * ' ' , ' \ \ W \ ■ ' • 208 INFLAMMATION i't. it only be the manifestation of local increased activities of cells. In animals it is quite possible, nay probable, that, where the irritation is not too severe, the increased metabolic changes in the cells tend towards katabolism and liberation of heat ; but if so, this is so slight, and the heat is so rapidly diffused into the circulating blood, that thermometric measurements fail to give evidence of its existence. It may thus be left out of consideration for practical purposes. 4. The increased temperature of superficial areas when inflamed is due, not to the production of heat in the part, but to the increased quantity of blood passing through it. When the congestion is so great that stasis ensues, there may be actual decrease in the temperature of the part. 5. The maintenance of high external temperature may exert a favourable effect upon the duration and progress of specific inflammation. Thus Filehne (211) has shown that the course of experimental erysipelas in rabbits is more rapid and more benign when they are kept at a high temperature than at a low. We possess no clear evidence that this is due to the unfavourable effect of the heightened temperature on the growth of the microbes. Pasteur's well-known experiments (212) upon the production of anthrax in fowls (ordinarily insuscept- ible to this disease) by lowering their temperature can be explained on other grounds. We have abundant evidence that heightened temperature promotes vascular dilatation : the experiment of Pilehne may therefore supply a further demonstration of the favourable effects of dilatation of the vessels and hypereemia of the inflammatory process ; indeed the use of hot air and electric light baths for this purpose is now strongly commended from many quarters. 6. Low external temperature, or the application of cold to the surface, contracts the vessels : hence, upon Digitized by Microsoft® cii. XXIV INCEEASED TEMPERATUEE 209 the lines of what has already been said, it would appear that (a) It is calculated to diminish the amount of exudation. (h) It has no directly good effect upon inflammation due to the presence and growth of pathogenic micro-organisms, but may have the reverse effect of preventing the fullest reaction on the part of the organism, (c) Where the irritant does not itself grow and multiply, or present cumulative action, there the application of cold may not only be of no harm, but of positive advantage, by lessening the inflammatory reaction and preventing this, where extensive, from being itself a cause of further injury to surrounding tissues. A further note upon this subject will be found in the chapter upon the Principles of Treatment (p. 227). Digitized by Microsoft® Digitized by Microsoft® PAET III GENEEAL CONSIDEEATIONS 211 Digitized by Microsoft® Digitized by Microsoft® CHAPTEK XXV ON THE VARIETIES OF INFLAMMATOEY MANIFESTATION There is but one process of inflammation, but the mani- festations of that process may be very various. Here I have only to indicate the main varieties. To give a complete classification is impossible unless each separate tissue be taken in order, for each tissue presents peculiarities either in liability to inflammation or in the course assumed by the process. Even to attempt a classification in broad outline is beset with difficulties, for the inflammatory manifestation varies, not according to one or two series of causes, but according to four at least ; the permuta- tions are thus so numerous, and the appearances so varied, that to give an adequate scheme of classification would require a diagram in four dimensions. These four causes of variation are — A. Nature of tissue affected. B. Position of tissue affected. C. Intensity of irritation, or, more correctly, ratio between resistant powers of the organism and intensity of the irritant. D. Nature of irritant, A. Nature of Tissue affected. — As I have already shown in the first portion of this study, there is in the earlier stages of the process a difference in the reaction of vascular and non-vascular tissues, the one series exhibiting marked congestion and vascular disturbance, the other not. At a later stage, or in more chronic 213 Digitized by Microsoft® 214 INFLAMMATION pt. m irritation, as new vessels invade the non-vascular areas, the changes in the two series do no doubt approximate ; but in the earlier stages we may distinguish between an ordinary inflammation and " inflammatio sine in- flammatione." The relative denseness and compactness of the tissues also introduce characteristic alterations : a dense tissue, such as bone, does not show the signs of reaction to injury to nearly the same extent as does a loose tissue — such as the omentum, for example — thus, in the former there may be a process almost as atypical as in non- vascular areas. The rigid framework of a tissue like bone prevents great vascular dilatation and exudation, but at the same time may be the seat of great pain due to action of the concentrated irritant upon the nerve- endings. The loose connective tissue of a structure like the omentum, on the other hand, permits great exudation with little or no pain. The influence of structure is well seen in comparing the course of inflammation afl'ecting cutaneous, mucous, and serous surfaces respectively. Where we have to deal with cutaneous surfaces, or surfaces formed of squamous epithelium, there the increased exudation, and the resistance offered by the layers of flattened cells to the free exit of the exuded fluid, lead towards the forma- tion of vesicles or blisters. In the case of serous surfaces, which form the walls of a moist cavity, the irritant, affecting primarily but one portion of the surface, is very likely to be borne into the cavity with the exudate and to set up an inflammation extending over a very large portion of the surface. Mucous and cutaneous surfaces, which are not thus the boundaries of cavities, exhibit a more marked disposition to the production of localised inflammation and of ulcers ; the superficial layers indeed of a well-formed epithelium or mucous membrane, by the Digitized by Microsoft® CH. XXV INFLAMMATORY MANIFESTATION 215 protective powers of their cells form a defence against irritation from without : thus the superficial exudate from a region of local inflammation cannot easily produce a superficial extension of the process. Not only the nature of the tissues, but their function also, profoundly affects the character of the inflammatory manifestation. Thus, excretory organs, by the very nature of their function, during the attempt to remove noxious substances from the system, are especially liable to generalised parenchymatous inflammations, — the irrita- tion not being local, but affecting at the same time all the cells whose part it is to take up and excrete the irritant bodies. B. The position of Tissues. — It is difficult to con- sider the position and relationship of tissues as they affect the inflammatory manifestations, without continually touching upon their structure. Nevertheless, the two, though very closely connected, do not go hand in hand. A familiar instance of modification in form brought about by position is to be seen in the result of suppurative inflammation — in the development of ulcerous conditions when the process affects free surfaces, of abscesses when it attacks deeper tissues. The process in the two cases is virtually the same : there is the same abundant deter- mination of leucocytes, the same degeneration of them into pus. Yet apart from the gross difference in form there are minor differences between the two. There is, for instance, relatively much more serous exudation from the free surface of an ulcer than there is into and around an abscess. As a general rule, inflamed tissues near a free surface are the seat of more aljundant exudation. Of this liability for free surfaces to be the seat of serous inflammation I have already spoken. The skin, with its thick dermal layer, affords a good example : when the full suppurative stage is not reached, inflammation affecting Digitized by Microsoft® 216 INFLAMMATION pt. m the outermost layers of the derma is most often of a vesicular or oedematous character ; when it afifects the deeper layers of the derma tlie serous infiltration is less evident. Yet another example of the influence of position in modifying form is seen in enteric fever. In this malady, the lymphoid tissue forming Peyer's patches becomes the sea.t of excessive cellular infiltration and proliferation, undergoes necrosis, and is cast off, leaving the well- known ulcers. The lymphoid tissue of the neighbouring mesenteric glands likewise undergoes great infiltration and enlargement, but necrosis rarely implicates the whole of a gland : notwithstanding the previous extensive in- flammation, the glands commonly recover their normal appearance and size. Beyond this there are few broad principles to be laid down concerning the relationship between forms of inflammation and position that do not essentially depend upon the structure and functions of the tissues. Much can be said concerning the intimate connexion between position and liability to inflammation ; but this and the allied and most important subject of the protective mechanisms of sundry tissues against injury are away from our present point. 0. The Relative Intensity of the Irritant is a more frequent and potent cause of variation. I have already in several places referred to the ratio between the resistant powers of cells and the intensity or virulence of the irritant as it affects the inflammatory process, and have shown how much that was previously vague has been made clear by bacteriological research ; while, at the same time, it has brought home the. truth that there is a single process of inflammation, the manifestations of which while varying merge insensibly the one into the other. Digitized by Microsoft® CH. XXV INFLAMMATOEY MANIFESTATION 217 Broadly speaking, it may be stated, as a result of these sti;dies, that, cceteris paribus, increased virulence of any given microbe or diminished power of resistance on the part of the organism or of the tissues, leads to corresponding alterations in the phenomena of inflammation at the region of inoculation ; and vice versa. Thus, if a pathogenic microbe, such as that of anthrax or erysipelas, be greatly attenuated, the effects of inoculation into the subcutaneous tissues may be scarcely recognisable. If the attenuation be not so extreme, some hypertemia, a determination of leucocytes, and, relatively, very little exudation, will be seen ; and in the course of a day or two all traces of inflammation may have disappeared. With slightly more virulent microbes the migration of leucocytes may be followed by their breaking down and consequent abscess -formation ; with further increase of intensity of action the migration of leucocytes may be wanting, while the exudation extends and the inflammation rapidly spreads and leads to a bacteritemia. A like series of changes is observable if the strength of virus be constant and animals more and more susceptible (or less and less refractory) be inoculated. The variation in tubercular lesions, from isolated dense fibroid masses to loosely formed cell-accumulations and diffuse tubercular inflammation, is evidently explicable on this law. The law holds good also, not merely for bacterial products, but for other irritants. The effect of croton oil varies with the strength of the solution applied ; and, as shown by Samuel, according to the condition of the animal. The same is true of abrin and other vegetable extracts. Turning to physical irritants, while here the intensity of the irritant alone or almost alone is called into play, numerous examples can be given of the effects of variation in this one respect upon the inflammatory manifestation — Digitized by Microsoft® 218 INELAMMATION ft. m effects of cold, for instance, varying from chilblain through inflammatory cedema to gangrene ; of heat varying from hypersemia through vesicular inflammation to complete destruction of tissue ; and, again, effects of caustic substances. In this era of aseptic surgery we may forget what was well known to the last generation of surgeons, that caustic substances may be employed either to originate a benign and reparative inflammation (as in the case of indolent ulcers), or, in larger quantities or greater intensity, to bring about a state in which the death of the tissue -elements is far in excess of the subsequent repair. Thus then, according to the above- mentioned ratio, inflammation in a tissue may vary by insensible gradations from a mere hyperemia up to a spreading suppurative or gangrenous process ; and from a purely local manifestation to the development of what may be termed an inflammation of the whole organism. D. The Nature of the Irritant. — It is clear, then, that it is impossible to base a classification upon the nature of the irritant : the attempt to mark off sharply the inflammations caused by mechanical and chemical noxffi from those produced by bacteria and their products must be given up. Hiiter's proposition that suppuration can only be induced by microbes has been repeatedly shown to be erroneous. Thanks more especially to the researches of Councilman, Leber, Grawitz and de Bary, and Straus (many more names might be mentioned in this connexion), we now know that many chemical substances are capable of causing pus- formation. Among these may be mentioned turpentine, croton oil, mercury, copper, and silver nitrate. While this is so, it must be borne in mind that under ordinary conditions these sub- stances very rarely act upon the organism in a state of sufficient concentration to be pyogenic. Thus, while it is impossible to make a sharp line of demarcation Digitized by Microsoft® cH.xxv INFLAMMATOEY MANIFESTATION 219 between bacterial and chemical irritants, it holds true in the main for man that suppurative disease is an indication of the presence and growth of microbes. On the other hand, although this pyogenic property is not confined to microbes and their products, yet among microbes it is not the common property of all. Some, like the bacillus of tetanus, never in themselves induce pus - formation : others, like the bacillus of tuberculosis, lead characteristic- ally to tissue-growth and the formation of inflammatory neoplasms rather than to pus-formation. Even among those which, like the micrococci, are highly pyogenic, the formation of abscesses only occurs when there is a definite relationship between the virulence of the microbe and the resistance of the organism. The reverse is equally true, that numerous microbes, not specially pyogenic, produce pus under peculiar conditions. Thus, the bacillus typhosus, when it multiplies in the middle ear, induces a suppurative otitis, and is further capable of originating a suppurative arthritis and the formation of abscesses in various tissues. In fact, under varying conditions the same microbe can induce very various forms of inflammation. Thus, Charrin (213) has shown that the B. pyocyaneus and its products are capable of inducing in one organ — the kidney — -pathological conditions so diverse as acute, chronic, parenchymatous, interstitial, and thrombotic nephritis, with, in addition, cyst-formation and amyloid degeneration.^ This same microbe can induce acute suppuration in the anterior chamber of the eye ; and when inoculated into the blood cause a hjemorrhagic inflammation of the serous surfaces. Hence we can proceed farther and state that no strict classification of inflammation can be made according to the nature of the ^ These changes are comparable with the diverse conditions of the kidney in the human being brought about by the scarlatinal virus. Digitized by Microsoft® 220 INFLAMMATION ft. m bacterial irritants ; it is, however, possible to make a general grouping of those affecting man, as follows : — (i.) Micro-organisms characteristically leading to pus- and abscess-formation — Staphylococci and streptococcus pyogenes, B. anthracis. (ii.) Those leading to abundant exudation with necrosis — B. of malignant oedema. (iii.) Those leading to cellular infiltration without usually causing abscess formation — B. typhosus, M. gonorrhoeae, B. diphtheriae, etc. (iv.) Those inducing characteristically the develop- ment of inflammatory neoplasms — B. tuberculosis, B, pseudo-tuberculosis, B. mallei, Actinomyces, Aspergillus fumigatus. Similarly, chemical substances may roughly be grouped into — (a) Substances causing so slight an irritation when introduced into the organism as to induce cellular over- growth only in their immediate neighbourhood — such as bland foreign bodies, bullets, etc. ; inhaled particles of coal, stone, iron, and the like, conveyed into the pulmonary lymphatics. (&) Substances leading to vesicular inflammation, for example, blistering agents, such as cantharides. (This result, however, depends more upon the position than the nature of the irritant.) (c) Substances leading to cell-necrosis, followed by the formation of granulation-tissue — caustic agents. (d) Substances leading to cell-necrosis and suppura- tion, such as copper, mercury, mineral acids, etc. (a very rare result in man). These lists, from the considerations given above, are necessarily unsatisfactory and imperfect. Other Considerations. — Among other factors modify- ing the inflammatory process may be mentioned the Digitized by Microsoft® cH.xxv INPLAMMATOEY MANIFESTATION 221 duration of the action of the irritant, which of necessity must modify the extent of the manifestations of dis- turbance in the tissues. A simple aseptic incision, for example, leads to a much milder and slighter series of changes than do the prolonged presence and growth of the tubercle bacillus. And in general it may be stated that mechanical causes of injury set up the simplest forms of inflammation — those unaccompanied by suppura- tion, unless secondary infection ensues. To state, as laid down by some authorities, that mechanical injuries do not induce inflammation, is wholly opposed to the con- ception of the process here accepted. Even the simplest fracture of a bone, for instance, is followed by dilatation of the vessels of the surrounding parts, by exudation, diapedesis of leucocytes, and indeed by all the cardinal symptoms whether of the old or the more modern school. While at iirst it might appear an easy matter to name case after case where the irritant has but a momentary action, upon further consideration it is found that, in the majority of cases of purely mechanical injury, this is not the case ; or, to express the matter more exactly, in the case of physical injuries, it is not the act of wounding that causes the inflammation, but the damage inflicted upon the cells of the tissues ; as, to a very large extent, inflammation is set up by the products of the injured and destroyed cells. A bone may be suddenly broken, and, nevertheless, even in the most favourable circum- stances, pain, swelling, and congestion may affect the region of fracture for several days. One or other region of the body may be rapidly frozen : the inflammation does not manifest itself till after the physical agent has ceased to act, but it continues for hours, and even for days. There are, moreover, physical irritants of another nature producing definitely chronic inflammation ; I refer Digitized by Microsoft® 222 INFLAMMATION pt. m to foreign bodies which have gained an entrance into the system. These if bland in themselves may nevertheless cause irritation. A good example of the extensive inflammation which such bodies may set up is seen in the dense fibrous interstitial tubercular masses developed in the lungs of stone-masons around fine silicious particles carried into the lymphatics from the alveoli. From such examples it will be evident that no satisfactory distinctions between bacterial irritants on the one hand, and physical irritants on the other, can be founded on the duration of irritation. This factor plays no easily recognised part in determining the various forms of inflammation, and consequently I have forborne to place it in the list at the beginning of this chapter. In thus passing rapidly over the iiifluence of each of the four main causes of variation I have of necessity excluded sundry forms of inflammation due to the com- bined action of two or more. There are, for instance, such well-marked forms as the catarrhal and croupous, due to the interaction of all four factors : embolic inflammation and lymphangitis have also been passed over ; these, however, are not so much forms of inflamma- tion as inflammatory processes occurring in special regions as a result of special methods of conveyance of the irritants. The factors then are so many, and their interaction so varied, that anything approaching to an orderly classifica- tion is hopeless. What I have here written must be regarded, not as an attempt to formulate such a classifica- tion, but as an attempt to indicate briefly how the nature and position of the tissues and the nature and intensity of the irritant bring about modifications in the process of inflammation. Digitized by Microsoft® CHAPTEE XXVI ON SYSTEMIC CHANGES CONSEQUENT UPON INFLAMMATION The results of an acute local inflammatory process are not confined to the immediate locality, but associated alterations in the system at large have long been recognised ; yet while recognised these systemic changes have been but little studied : I cannot pass the matter over in silence, but my setting forth of it must necessarily be very brief and imperfect. I cannot here say more upon the effect of local irrita- tion on the nervous system than that, apart from direct reflex action leading to changes of nervous origin in the region of injury and the reflexes affecting associated regions, the higher centres, and through them the system at large, may become affected by paths that it is not always easy to trace. The disturbances of the nervous system which accompany local injury can be but vaguely and in- definitely described. As regards the secondary effects, the most suggestive work of the late Prof Eoy and Dr. Cobbett (214), and more recently of Crile (215) upon Shock, indicate that there is here a rich field for yet further research. Of the changes in the general circula- tion, and more especially in the circulating blood, thanks to the observations of von Limbeck (47), Eieder (216), Lowit (217), and Sherrington (218) we possess more 223 Digitized by Microsoft® 224 INFLAMMATIOlSr pt. m exact knowledge ; in acute local inflammation of some extent the circulating blood becomes inspissated : by- exudation it loses some of its plasma, while the more solid constituents — the red corpuscles — do not escape. The amount of fluid lost to the circulation is not equalised by increased entrance of lymph into the circulation : in one experiment of Sherrington the blood remained apoplasmic (that is, its specific gravity remained heightened) for more than sixty hours after the infliction of injury. This apoplasmia or diminution in the relative amount of plasma in the blood appears to depend in some measure upon the extent of the vascular area involved in the inflammation ; for example, Prof. Sherrington shows that when both feet are involved, by plunging the limbs in water at 52° C, the apoplasmia is more severe than in experiments affecting one foot only. Another well-marked change in the blood concerns the leucocytes. As suspected by Lowit and proved by Sherrington, there is, in some forms of inflammation at least, a primary diminution in the number of leucocytes per unit volume of blood (leucopenia), followed by a marked increase in the number of leucocytes in the blood (leucocytosis). The number or leucocytes was in some instances increased sevenfold. In the leucopenia of inflammation, the diminution is chiefly confined to the polymorphonuclear leucocytes. These observations of' Sherrington are confirmed by the observations of Everard, Demoor, and Massart (219). Whether the diminution be due to disintegration, or to collection in some area of the circulation, is not yet wholly determined ; the observations of Muir and others favour the latter view, and indicate the lungs as regions in which the accumulation occurs. The leucocytosis may become obvious within an hour after the establishment of a local lesion ; and it may be prolonged for several days. Digitized by Microsoft® OH. XXVI ON SYSTEMIC CHANGES 225 even in cases where the injury has been of a mechanical nature. Here, again, according to most observers, it is chiefly the polymorphonuclear or finely granular oxyphil cells which increase in numbers. It is interesting to note that coinoidently the coarsely eosinophil cells appear to undergo great diminution ; in peritoneal lesions these accumulate in the omental and mesenteric capillaries (86). I can do no more than point out the existence of these blood changes, and further that changes in the number of leucocytes in the blood are not wholly accounted for by the number passing from the blood into the inflamed area. It would seem that local inflammation in some way brings about an over-stimulation of lymphoid tissue, notably that of the bone-marrow, whereby an increased number of leucocytes are poured into the blood. It is generally accepted nowadays that the process is essentially chemiotactic, the circulating products of tissue disintegration and toxins attracting the leucocytes from the bone marrow into the capillaries. Certainly the direct introduction of the products of bacterial growth into the circulating blood may lead to a more or less pronounced and rapid diminution of the number of leucocytes in the blood, and this diminution, as shown by Lowit, may be preliminary to a subsequent increase. The further important general disturbance associated with local injury, more especially when of bacterial origin, namely, the occurrence of fever, cannot here be considered. Bacteriological studies lead to the conclusion that traumatic fever, at any rate, is largely due to the diffusion in the blood-stream of soluble bacterial products, and of the products of tissue-destruction derived from the inflammatory focus. Here may be noted a suggestive after-result of local infection seen in certain diseases. It is a well-established fact that the presence of one developed primary syphilitic Q Digitized by Microsoft® 226 INFLAMMATION pt. m lesion, or chancre, renders it impossible for the individual to become reinfected and exhibit a second chancre in another region of the body. Certain more recent observations indicate that if less than eleven days intervene between the first and subsequent inoculation double infection is still possible. Koch has shown that the same largely holds true in connexion with tubercu- losis in the animals of the laboratory. The only adequate explanation of this phenomenon would seem to be that with local growth of the specific organisms there is this same diffusion of the toxins into the lymph and blood and with this a progressive immunization of the tissues elsewhere. Nay more, it is becoming increasingly recog- nized that the febrile rise of temperature is an indication of increased metabolism, favouring (within limits) the production throughout the organism of " antibodies " and the neutralisation of the toxines, both at the seat of their production and diffused. Digitized by Microsoft® CHAPTEE XXVII ON THE PRINCIPLES OF TREATMENT The subject of treatment is not in any way part of a treatise on the pathology of a given condition. It has, however, to be acknowledged that if the views here propounded and the conclusions reached be correct, they must have a very direct bearing upon the principles of treatment, and a few words must be said regarding those principles. If, in the past, when inflammation was regarded as in itself a harmful process, treatment was nevertheless successful, it is obvious that principles and practice cannot have gone wholly hand in hand, and, conversely, that if treatment was carried on with the idea that the process was in itself dangerous, then time and again procedures were undertaken which were not to the benefit of the patients. As a matter of fact, as already indicated, within the last few years extensive changes are coming into effect and are proving themselves advantageous — such as Bier's method of induced hypersemia, von jMikulicz's of injections to develop the "resistance period," Wright's method of employing the toxins of specific microbes to stimulate increased resistance to the local growth of these microbes, all of which are based on the assumption that inflammation is the reaction to injury, and demand that the right method is not to lessen or arrest but, on the contrary, to stimulate and augment that reaction. 227 Digitized by Microsoft® 228 INFLAMMATION pt. hi I have recently, in Keen's System of Burgery, discussed, at some little length, the application of these principles to treatment. Here I would briefly recapitulate what appear to me the more important deductions. " Inflammation is a danger signal, but by no means necessarily a danger. Wherever we observe the outward and visible signs of inflammation we have the indications that something abnormal has occurred in the tissues, something which has brought about a reaction on their part." Thus it is our duty to determine as soon as possible what that something is. If we incise or other- wise operate, our object must be not primarily to reduce the inflammation but to remove the irritant. If we determine that operation is inadvisable, then first we must secure physiological rest for the inflamed part, so that there be no waste of energy on the part of the tissues, that energy being devoted to its fullest to counteracting the irritant. Of equal importance are procedures calculated to improve the general bodily state and promote the wider reaction on the part of tissues at a distance. Here I may refer to my remarks regarding cryptogenic infection (p. 236), and to the necessity of guarding against not merely the entrance into the injured area of bacteria by way of the blood-stream, but also of toxins and deleterious diffusible substances from the same source. From this it follows that the general health of the patient must be fostered ; the external hygienic condition must be made as good 'as possible ; the food given be bland ; the bowels be kept open, and the other excreting systems brought, where possible, into free action. Where in addition to local injury the development of fever indicates that toxins are becoming diffused from the inflammatory focus, it is necessary to proceed further and promote, not merely free, but increased excretion through Digitized by Microsoft® OH. xxvii PEINGIPLES OF TREATMENT 229 the kidneys, bowels, and skin, by the employment of copious fluid given by the mouth (or in the form of enemata or subcutaneous injections), of diuretics, sudorifics, etc. What steps shall be taken in addition to these general procedures must be determined by the extent of the reaction observable. All must, depend upon whether that reaction is , i. Adequate, ii. Inadequate, iii. Excessive. i. The cases of adequate reaction are those which many surgeons in the past have been inclined to exclude from the category of inflammations, and that because they call for no operative interference. Here are to be included the natural, uneventful healing of wounds, fractures, etc. Save for measures calculated to promote general and personal hygiene and physiological rest, such cases are wisely left to nature. ii. Inadequate. Paradoxical as it may seem, the majority of cases of pronounced inflammation are examples not of excessive but of inadequate reaction. The very extent of the disturbance and its tendency to spread are in themselves indications that the system is for the time unable to counteract the irritant. The irritation may be excessive, but that is another matter. Hence the indications are (1) if possible to remove the irritant ; (2) to promote and not reduce the inflammatory manifestations ; (3) to aid as far as possible the general reaction on the part of the organism. Here we have the rationale of Bier's treatment (132), which seeks (and in favourable cases with great success) so to promote the hyperBernic exudation and inflammatory reaction in general, that the first mode of combating the disturbance — that of operative removal of the irritant— becomes Digitized by Microsoft® 230 INFLAMMATION pt. m unnecessary.^ Wright's method of cure by injection of toxins comes under the third heading. In this connexion it may be pointed out that poulticing, the employment of hot compresses, etc., are all means which have been employed for generations to " bring an inflammation to a head," i.e. to promote an adequate reaction. The employment of simple laparotomy to heal local abdominal tuberculosis is another example of the same principle, i.e. the mere act of exposing the abdominal contents, whether these be healthy or diseased, causes an augmented inflammatory reaction. iii. Beaction in excess is the exception, not the rule. We do not observe it in the early stages of the process so much as in the later, in the production, for example, of exuberant granulation tissue, in the development of keloid, in the prodactive overgrowths of chronic inflam- mations, which, as we have pointed out, appear to pass imperceptibly into the class of new growths, and are to be regarded as indicating an idiosyncrasy on the part of the tissues of the individual whereby a minimal irritation has initiated persistent overgrowth. At most we note in acute cases that one factor in the process may be unduly exalted as compared with others, so that the vitality of the tissues is imperilled — excessive hypersemia may pass on to stasis and necrosis, there may be excessive deposit of fibrin, and so on, — and means, where possible, must be taken to regulate the process. Another group of cases would seem undoubtedly to be the series of sympathetic or referred inflammations, in which parts, whether sur- rounding the injured area, as in the case of the joints, or at a distance, but innervated from the same region of the cord, show the symptoms of an acute inflammation when ' Where, however, there has ah'eady developed a suppurative focus, or abscess, Bier now recommends the free removal of the pus in addition to the hypersemic treatment. Digitized by Microsoft® CH. xxvii PEINCIPLES OF TREATMENT 231 they themselves have undergone no direct irritation. A knee, or an ankle, for example, vfhich has suffered a relatively slight mechanical injury of the joint-surfaces or ligaments, may rapidly present intense swelling and redness of the surrounding parts. Such in the absence of any treatment tends to bring about immobilisation and physiological rest, but where recognised it may safely,^ I think, be dispensed with, provided physiological rest may be gained by other means. It is in these cases of excessive hyperemia tending towards stasis (as suggested to me by my colleague, Dr. G. Armstrong) and of referred inflammation, that the reduction of the hyperaemia by the application of cold would clearly seem to be the proper practice. In chronic inflammation it cannot be said that there is any direct treatment. If fibrosis has occurred we cannot directly cause its absorption. We have, it is true, evidence that fibroid tubercles and fibroid adhesions may eventually disappear ; we cannot bring about this result with certainty in any particular case. At most we can endeavour to improve the circulation in general, and by that and other means improve the vitality of the tissues and favour the removal of the irritant, as also by the employment of drugs, such as potassium iodide, we can strive to promote absorption. Electricity, active and passive movements, and massage are all useful auxiliaries. Vesicants, rubifacients, setons, and counter-irritation have all been employed towards the same end. Digitized by Microsoft® CHAPTEE XXVIII ON ADAPTATION : CONCLUSION It will be seen that the picture of inflammation here given is very different from the old view in which the dominating idea was that inflammation is essentially an injurious process leading to cell- and tissue-destruction. Here we regard the irritant as capable of causing cell- and tissue-destruction, and so long as the irritant is in action so long may this destruction continue. But inflammation itself we regard as the series and sum of the reactive processes set up in the tissues, and then bringing about, not destruction, but the very reverse. Takin" as our definition that inflammation is the o response or reaction to injury, we are inevitably led to see that this response results in counteracting, or more exactly in tending to counteract, the deleterious effects of the irritant ; the inflammatory process tends towards repair. It may not result in repair, for, as we have pointed out in several instances, too often the reaction is either inadequate or excessive. The exudation may possess but slight bactericidal powers, or may be poured out in such quantities that the microbic irritant, instead of being retained in the region of injury, is conveyed outside that region ; the wandering cells, instead of destroying, may undergo destruction ; they may in- corporate bacteria, but not be able to annihilate them ; 232 Digitized by Microsoft® OH. XXVIII ON ADAPTATION 233 the fixed cells may either form an incomplete cicatrix, or continue to proliferate in excess. Attempt at repair is not repair. Notwithstanding, studying the various factors involved, it is forced more and more upon us that each tends in one definite direction, and the sum of the processes is reparative. This conception of the process of inflammation has met with considerable opposition. It is urged that, to consider inflammation as an attempt at repair is teleo- logical, i.e. is to assume that each reaction in the process is, in itself, purposeful. And, carrying this objection to its ultimate end, " you conceive," say the critics, " that the leucocyte is endowed with intelligence so that it recognises in the microbe a foe to the organism ; scents it from afar ; hunts, seizes, and digests it, and then, its duty done, its mission in life fulfilled, it withdraws its pseudopodia and dies contentedly." It is needless to say that we hold no such views regarding the intelligence of the leucocyte. At the same time we unhesitatingly regard inflammation as purposeful — every whit as much as we regard the iris, with its contraction and dilatation under different intensities of light, as subserving a purpose, or the acts of feeding and digesting as being with purpose. Inflammation is a physiological process in so far as it is the calling into action, in response to accustomed stimuli, of properties normally possessed by the tissue ; it is a pathological process in so far that, while the stimuli are in kind not different from normal stimuli, in intensity they are greater. If we admit physiological purpose, we must admit pathological. This may, indeed, be laid down regarding all pathological conditions, namely, that in them we are not dealing with the effects of new and unaccustomed factors, but with the ordinary factors telling iipon the tissues in an abnormal way, being either Digitized by Microsoft® 234 INFLAMMATION pt. m deficient or excessive in their action. Within physio- logical limits, the reaction to a given stimulus is nicely balanced and adequate ; when the stimulus is excessive, the reaction is liable to be imperfect. The iris accommo- dates and adequately protects the retiua within certain limits, but, if the eye be exposed to too intense a light, the iris fails to arrest all the rays and the retina suffers. And so it is that, in inflammation, when the stimuli are excessive and so have become irritants, the tendency is for the reaction not to be perfectly balanced, and the ultimate result to be an incomplete counteraction of the disturbance. But, to repeat, if we recognise purpose in the one set of cases, we must recognise it in the other. All, it will be seen, depends upon what is our con- ception of "' purpose " in vital phenomena. That con- ception is teleological if and when we regard it as primary — as what may be termed an intelligent endeavour on the part of the tissue to accomplish a certain object — a predetermined end. To suppose that, in inflammation, the vessels dilate and bring about increased exudation in order to flush out the iriitant, is an utterly wrong and baseless idea. If, on the other hand, our conception is along these lines — that in the course of evolution those individuals survived who, by chance, let us say, happened to manifest this reaction on the part of their vessels in response to stimuli of a certain order, whereas those who did not were more unfavourably placed and so succumbed ; that they conveyed the same power to their_ descendants who also possessed this advantage over individuals incapable of affording the reaction ; then we can conceive the development of a race possessing a mechanism for countering a given stimulus by a given reaction, a race in which provision is made, or gained, for dealing with a given order of events ; then it will be seen that what primarily is accidental becomes secondarily purposeful Digitized by Microsoft® CH. xxviii ON ADAPTATION 235 through the survival of tlie fittest and the inheritance of defensive acquirements. The tissues thus become pre- pared to respond to certain alterations in their environ- ment. In other words, " natural selection " renders what was primarily accidental, secondarily purposeful. The whole process of inflammation is an exemplification of " adaptation," and we would strongly commend the address by Prof. Welch (220) upon this subject to those desirous of gaining a right point of view regarding patho- logical processes in general. For living matter to survive, it must he adapted to its environment, and this, in the first place, happens through inheritance, through the survival of the fittest, along the lines laid down above. Yet, in the study of inflammation, we are compelled to recognise, not merely inherited, but also individual adaptation. We cannot otherwise explain why it is that bacteria, which at first exhibit active local growth within the tissues, become eventually destroyed on the resolution of the inflammatory state, unless we acknowledge that the cells, or certain of them, acquire and, it must be, transmit, increased bacteriolytic and antitoxic properties. The facts gained regarding the development of immunity — the presence in the body-fluids of the immunised animal of substances inimical to the infective agents, which are absent, or present in but minimal amounts, in the fluids of the untreated animal — all demonstrate this individual adaptation. At the present time, indeed, workers all over the civilised world are busy in researches bearing upon this very subject, the production and mode of action of what may be termed, generically, anti-bodies. Here I can do little more than mention certain general laws which seem to be at work in bringing about, or favouring, individual adaptation. 1. The first is that of reserve foree. No cell — and' no tissue — normally is in action to the limit of its Digitized by Microsoft® 236 INFLAMMATION pt. m powers ; on the contrary, normal activity is far below what the cell is capable of performing. In other words, normal stimuli do not induce a maximal reaction, and, therefore, irritants — excessive stimuli — up to a certain limit, do not overwork, and do not lead to disintegration of the cell. Perhaps the greatest difficulty encountered by most students of medicine in accepting the facts of phagocytosis lies in this, that, regarding the tissues as normally sterile, they cannot comprehend the assumption of what appear to be totally new properties by the leucocytes and other cells in inflammation and infection, namely, the assumption, as they regard it, of phagocytic powers and the taking up of pathogenic bacteria. But, as a matter of fact, this is no new property. Throughout life the cells are engaged in digesting bacteria. We find phagocytic leucocytes passing out and free upon mucous surfaces — any smear or swab from the pharynx will show these leucocytes with their contained bacteria. As Paiffer (221), Nicholls (222), and others have shown, bacteria are to be seen in the lymph-glands and along the lymphatic channels of healthy animals, and these, most often, within cells. As Ford (223), working in my laboratory, has demonstrated, using the fullest precautions against contamination, bacteria can be cultivated from the liver and kidneys of more than 5 per cent of the appar- ently healthy animals of the laboratory ; and that the bacteria so obtained are not contaminations is proved by the remarkable regularity with which each different species presents a difierent bacterial flora. Having followed Ford's observations and seen the care with which they were conducted, I cannot accept the observations of those who refute his work. As Wrosczek (224) has recently shown, if animals be fed with non-pathogenic germs, or germs setting up no recognisable intestinal disturbances, colonies of the species so injected are, later, to be gained from the Digitized by Microsoft® CH. xxviii ON ADAPTATION 237 various organs of the apparently healthy animals. The tissues are potentially sterile ; that is, the leucocytes and other phagocytic cells are, throughout life, engaged in destroying hacteria which have gained occasional entrance .into the tissues (225). When a few intensely virulent bacteria gain this entrance, or a large number of a less virulent form manage to grow in some one or other locality, and thus set up inflammatory changes, the above- mentioned reserve force in the phagocytic cells comes into play and permits these cells to take up and digest the greater numbers or the more toxic forms. It is this circulation of potentially pathogenic microbes that ex- plains the cryptogenic infections of internal organs. 2. The second law is that of accustomance. A cell not actually destroyed by any deleterious agency is apt to become accustomed to the presence and action of that agency. What is the basis of this accustomance it is difficult to say, though it is not difficult to suggest a hypothesis or hypotheses. Here I simply state that this is an observed law, a law best exemplified in what has been made out regarding the conversion of a negative into a positive chemiotaxis. 3. The third and very important law, somewhat closely allied to the last, is that of habit, or, as Fraser Harris (226) has termed it, ''vital inertia." According to this law, when once, through a given stimulus, a certain series of molecular changes is set up in a cell, those changes are liable to continue after the stimulus has ceased, and, if the stimulus be sufficiently strong or sufficiently often repeated, the cell acquires the habit, or property, of setting in action a particular series of molecular changes after a minimal stimulation. This is, perhaps, best exemplified in connexion with our subject in the production of antitoxins. It is found that, once the diphtheric toxin, for instance, has stimixlated the cells Digitized by Microsoft® 238 INFLAMMATION pt. n of the organism to produce antitoxins, that production continues and is wholly out of proportion to the amount of toxin introduced ; while, similarly, once an animal has gained full immunity against any organism, it only needs the introduction of that micro-organism into the system to induce an immediate reaction, whereas previously days or weeks had been required for accustomance and counter- action to be adequately developed. The existence of this law was first recognised by Weigert (183); it may be said to form the basis of Ehrlich's side-chain theory of immunity.'^ Hence, to sum up, while I would not give this as a definition (as I did in a previous edition), for I see the force of Ainley Walker's argument that, in a definition, one should state what a thing is and not what it tends to bring about, — my conception of inflammation, from all the considerations here laid down, must be that it is the series of changes constitutiiig the local manifestation of the attempt at repair of actual or referred injury to a part, or, briefly, as the local attempt at repair of actual or referred injury. And in conclusion let me lay stress upon what I regard as the main outcome of this essay. In studying the reactions of the organism to injury, we must be impressed by the multifariousness of natural processes ; the end may be attained, not in one way only, but in many. It is not by cells of one order alone — by phagocytes — or by leucocytes in general and only leucocytes, or merely by the reaction on the part of the fixed cells of the tissue, or by vascular changes alone, or by altered temperature, or solely by the chemical and mechanical action of the exudate that repair is effected. All means are employed to antagonise the irritant and to effect healing. The 1 I have discussed more fully the principles underlying adaptation and the mode of its development in my Principles of Pathology, vol. i. p. 10] . Digitized by Microsoft® OH. XXVIII ON ADAPTATION 239 cells of the body, fixed and free, play their part ; the nervous system aids the process ; the bodily humours render efficient help ; modifications in the vessel-walls and blood-stream are valuable auxiliaries. Diverse processes are employed, now one more particularly, now another, according to the needs of the moment, but none ex- clusively. So diverse are the opinions of pathologists upon many branches of this subject of inflammation, and so great is the amount of recent research, that I can neither hope that all the conclusions here set down will gain acceptance, nor that in these pages, inevitably condensed as they are, I have succeeded in recognising and duly acknowledging all work of primary importance. In the rapid progress of our science, much, it may be, that is here set forth will be modified. Nevertheless I hold that the conception of the inflammatory process indicated in this article is that which embraces the largest number of like phenomena, and excludes most satisfactorily those which if associated are unessential ; as again that it is along the lines here laid down, namely by the study of cellular pathology in its strictest sense, that the surest advance has been and is to be made in our knowledge of this the dominating process in disease. Digitized by Microsoft® Digitized by Microsoft® REFERENCES 1. Sir J. Burdon-Sandbhson. Art. "Inflammation." Holmes' System of Surgery, 5th edit, London, 1888. — 2. Huter, C. Allgem. Ghirurgie, Leipzig, 1878 : Grundriss der Ghirurgie, Leipzig, 1880. — 3. Zahn. Inaug. Diss., Berne, 1871. — 4. Grawitz. Quoted by Lubarsch (71). — 5. Mbtchnikofp. La Pathologie comparee de V inflammation, Paris, Masson, 1892. English transl. by Starling, 1893. — 6. Adami. "The Dominance of the Nucleus," Brit. Med. Journ., 1906, ii. 1760. For this and other matters bearing upon cell pathology the reader may also consult the author's Principles of Pathology, vol. i. — 7. Greenwood (Miss). Journ. of Physiol, 1886, vii. 254; 1887, viii. 263; 1890, xi. 576; 1894, xvi. 441, — 8. Le Dantec. Ann. deVInst Pasteur, 1890, U.'ilZ ■,\8'd\,y. 163. — 9. Krtjkexbeeg. Untersuch. a. d. physiol. Inst. Heidelberg, 1878, ii, 273. — 10. Reinke. Untersuch. a. d. botan. Inst. Gottingen, 1881.— 11. Frosch. Gtbl. /. Bakt, 1. Abt., 1897, xxi. 926.— MoDTOsr. Ctes. rend. Soc. 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Journ. of Physiol, 1898, xxiii. 359 ; see also Hardy and Lim Boon Keng, ibid., 1893, xv. 361. — 46. Durham. Journ. of Path., 1897, iv. 370 ; see also Muir, Journ. of Path, and Bad, 1901, vii. 161 ; ilyid., 1900, vi. 394. — 47. Taylor, A. E. Contributions from the William Pepper Lab. of Clin. Med., Philadelphia, 1900, i. 148 (gives full Bibliography to date). For full studies upon the htemal leucocytes see also Ewing, Clin. Path, of the Blood, 2nd edit, Lea Bros, and Co., New York and Philadelphia, 1903; von Limbeck, Grundriss einerldin. Pathologic des Blutes, Jena, (sucoe.ssive editions), gives a very thorough study of this subject — 48. Schridde. Anat. Hefte, 1905, xxviii. 698, Miinchener med. JVochenschr., 1905, Nos. 26, 29, and 39, and ibid, 1906, No. 4. Also Verhandl der d. pathol Gesellsch., Meran, 1905. — 49. LTnna. Monatshefte f prakt. Dermal, 1891, xii. 296; ibid., xx. No. 7; Berlin. Idin. Woch., Digitized by Microsoft® EEFEEENCES 243 1892, xxix. 1242; ibid., 1893, xxx. 222; iUd., 1893, 222.— 50. VON Marschalko. Archiv f. Dermat, 1895, xxx. 3 and 241 ; Gthl. f. allg. Path., 1899, x. — 51. JusTi. Virchows ArcMv, 1897, cl. 197 ; for fuller bibliography see Bbattie, Jmirn. of Path., 1902, viii. 129. — 52. Wlassow and Sepp. Virchows Archiv, 1904, olxxvi. 368; A. Wolff. Arch. d. me'd. exp. et d'anat. pathoL, 1903, xv. 713; Berlin. Min. JVochenschr., 1901, 1290. — 53. Almkvist. Virchows Archiv, 1902, clxix. 17. — 54. Paltatjf. Second Inter. Congr. f. Dermat., Wien, 1892 ; Lubarsch- Ostertag JErgebnisse, Abt. 2, 1895, 261. — 55. Maximow. Zieglers Beitr., 5tli supplemental Heft, 1902 ; ibid., 1904, xxxv. 93. — 56. Beckton. Journ. of Pathology, 1909, xiii. 185. — 57. Rdffer. £.il£/., 1902, ii. 491 ; Quarterly Journ. of Micr. Sci., 1890, xxx. — 58. Mallort. Journ. of Exper. Med., 1898, iii. 611. — 59. Adami, Abbott, and Nicholson. Journ. Exper. Med., \%Q9, iv. 349. — 60. Wbriqo. Ann.de I'Inst. Pasteur, 1894, viii. 1 ; see also Lemairb, Archives d. mA exp., 1899, xi. 556. — 61. Behring and Much. Prager med. Wochenschr., 1904, No. 1. — 62. Gdlland. Lab. Reps. B.G.P. Edin., 1891, iii. 106 ; Journ. of Path., 1894, ii. 447 ; Journ. of Physiol, 1895-96, xix. 385 ; Saxer. Ctbl. f allg. Path., 1 896, vii. 42 1 ; Uskow. " The Blood considered as a Tissue " (Russian), 1890 : various papers by his pupils in the Arch. d. Sc. Biol, St. Petersburg, 1893 to 1897 ; for abstract see Taylor (47). — 63. Muscatello. Virchows Archiv, 1895, cxlii. 327; Geaser. Arch.f Min. Ghirurgie, 1895, 1. 887 ; D. Ztschr. f. Ghirurg., 1888, xxvii. 533; BoRST. Virchows Archiv, 1900, ,clxii. 94; see also Maeohand. Zieglers Beitrdge, 1889, iv. 1 ; Sitzungsber. der Gesellsch. gesammt. Wiss. Marburg, 1897, No. 3 ; Der Proxess der Wundheilung,Stuttga,it,1901; and Rolopp, Habilitationsschr., 1894, quoted by Ltjbarsch (71) — 64. von Brdnn. Zieglers Beitr., 1901, xxx. 417; Monckbberg. Zieglers Beitr., 1903, xxxiv. 484 (BuTTNBR, ibid., 1899, xxv. 453, gives full literature on this sub- ject to date: this article continues it to 1903). — 65. Badmgartbn. Arbeiten u,. d. path. Inst. Tiibingen, 1904, iv. 310; Gtbl f. allg. Pathol, 1904, XV. Ergiinzungsheft, 115. — 66. Peatt. Johns Hopkins Hasp. Reps., 1900, ix. 265. — 67. Metchnikopp. Biol Gtbl, 1883, 561 ; A. de I'l. P., 1892, vi. 1 ; Q.J.M.S. (new ser.) xxiv. 112; Barfurth. Arch. f. ndkr. Anat., 1887, xxix. 35; Griffiths. Journ. of Pathol, 1894, iii. 131. — 68. Ranviee. G. R. Acad, des Sciences, 1889, ex. 165. — 69. Marchand. Verhandl d. d. pathol Gesellsch., 1902, iv. 124 ; see also Der Prozess der Wundheilung (63) — 70. Saxbe. Anatom. Hefte, 1896, No. 19. — 71. LuBAESOH. D. med. TVock, 1898, 501, 523, 539, Digitized by Microsoft® 244 INFLAMMATION 553. A valuable discussion of modem problems in regard to the inflammatory process. — 72. Gkawitz. Virchows Archiv, 1896, cxliv. 1 ; D. med. Wochenschr., 1896, No. 26 ; tjher Lehen und Tod. Eectoratsrede, Greifswald, 1896. — 73. Cabot, R. C. Osier and M'Crae's System of Medicine, 1908, iv. 595. — 74. For a study of this form of cell see, more particularly, Arneth. Die Neutrophile weissen Blutkorperchen bei Infektionskrankheiten, Jena, Fischer, 1904, and D. m.ed. Wochenschr., 1904, 92. — 75. Hardy and Wesbrook. Journ. of Physiol, 1895, xviii. 490. — 76. Opie. Trans. Assoc. Am. Physicians, 1904, xix. 136 ; Joh?is Hopkins Hasp. Bull, 1904, 15, 71.— 77. Maximow. Gthlf Path., 1903, xiv. 87.-78. Other articles bearing upon mast-cells are : — Schbbibbr, ibid., 1903, xiv. 913; and LoBB, L., Journ. Med. Research, 1902, viii. 44. — 79. Other recent articles upon the plasma-cell deserving of note are Ehrlich. Virchows Archiv, 1904, clxxv. 198; Herbert. Monatsschr. f. prakt. Dermat, 1900, xxx. 313, and Journ. of Path., 1900, vii. 90. See also Taylor (47) ; Whitfield, Brit. Journ. of Dermatology, Jan^iary and February 1904, gives a good statement of the different opinions and observations regarding these cells. — 80. Behgbll. Miinchener med. Woch. — 81. Borrel. A. de I'l. P., 1893, vii. 593. — 82. Dubnschmann. Journ. of Path., 1894, iii. 118. — 83. Kndd Faber. Journ. of Path., 1893, i. 349. The literature regarding giant-cells is given by Marchand. Virchows Archiv, 1883, xciii. 518, up to 1883; and by Hektobn. Journ. of Exper. Med., 1898, iii. 21, up to 1898. — 84. Duval and White. Journ. of Exp. Med., 9, 1907, p. 352. — 85. Gabritchbwsky. A. de I'L P., 1890, iv. 346. — 86. Eoux. Trans. Internat. Gongr. of Hygiene, London, 1891, ii. 120. — 87. Pekelharing. La Semaine med., 1889, 184. — 88. Massart and Bordbt. /. d. I. Soc. roy. d. Sc. mM. et nat. d. Bruxelles, 1890, and A. de I'L P., 1891, V. 417. — 89. Buohner, H. Berliner klin. Wochenschr., 1890, No. 47. — 90. Kanihack. Medical Ghron., Manchester, N.S., 1894, i. 246 and 332. — 91. Wolff, A. Berl. klin. Wochenschr., 1904, xli. 1105. — 92. MacFadyen and Rowland. Gtbl. f. Bakt., 1900, xxx. 753; Lancet, 1900, i. 849 and 1130; Proc. R. S., April 5, 1900. — 93. METCHifiKOFP. L'Lmmunite dans les maladies infectieuses, Paris, Masson, 1902. This work, besides recapitulating the main data given in the former (5), gives in detail M. Metchnikoff's views upon immunity in general, with criticism of opposing theories and bibliographical references. — 94. Leishman. Brit. Med. Journ., 1902, i. 73. — 95. Issaeff. Ztschr. f Hygiene, 1894, xvi. 287.-96. Ncttall. Lbid., 1888, iv. 353. — 97. Tradbe and Gschleidbn. Jahresber. d. schlesisch. Oesellsch., Digitized by Microsoft® KEFEEENCES 245 1874, lii. 1V9.— 98. von Fodor. D. med. Wochenschr., 1887, 745.-99. NissBN, F. Ztschr. f. Hygiene, 1889, vi. 487. — 100. Behring and Nissen. Ztschr. /. Hygiene, 1890, viii. 424 ; Behring, D. med. Wochenschr., 1891, 655. — 101. Hankin. Proc. R. S. Land., 1890, xlviii. 93 ; Ctbl. f. BalcL, 1892, ix. 722 and succeeding volumes ; " Discussion on Immunity," Trans. Internat. Congress of Hygiene, London, 1891. (This important discussion gives the views of the opposing schools, cellular and humoral — of Eoux, Metchnikoff, Behring, Buchner, Hankin, etc, A comparison of the contributions to this discussion with those to the discussions on the same sixbject at the succeeding Congress at Budapest (1894), and at the Internat. Med. Congress, Paris (1900), is of great interest as showing the gradual change in opinions on these topics. Another discussion well worth reading is that held by the Pathological Society of London in 1892 {B.M.J., 1892, i. 373, 492, 591, 604), and Trans. Path. Sac, 1892). — 102. Bdchneb. Arch. f. Hyg., 1890, x. parts i. and ii. ; Gthl.f. Bakt, 1889, v. 817 ; ibid., 1890, vi. 1 ; Fortschr. d. Med., 1892, x. 319 and 363; Gtbl. f. Bait., 1894, xvi. 738, etc.; art. "Im- munity," Encyclop. Medica, Edinburgh, 1900, v. — 103. Vaughan, Victor C, and M'Clintock. Med. News (N.Y.), 1893, 701. See also Kossbl, H., Ztsch. f. Hyg., 1894, xvi., and Arch. f. Anat. u. Physiol, Physiol. Abt., 1894, 200. — 104. TizzoNi and Cattani. Berl. klin. Wochenschr., 1894, 64, 189, and 732. — 105. Ehrlioh. Gesammelte Ahhandlungen, Berlin. Translated into English by Bolduan, New York, 1908. — 106. The leading papers on bacteriolysis will be found in (93). — 107. Ribbert. Ber Untergang pathogen. Schimmelpihe im Korper, Bonn, 1887. — 108. Dbnts and Havet. La Cellule, 1894, x. 1. — 109. Buchner. Miinchener med. Wochenschr., 1894, xli. 469 and 497.— 110. Bail. Berl. klin. Wochenschr., 1897, xxxiv. 887. — 111. Sohattenfroh. Arch.f. Hyg., 1896, xxvii. 234; 1897, xxxi. 1 ; 1899, xxxv. 135. — 112. Van dbr Velde. Eef. in La Cellule, 1894, x. 1. — 113. Jacob. Ztsch. f. klin. Med., 1897, xxxii. 466. See also Hahn. Munch, med. Wochenschr., 1897, xliv. 134; Lachtchenko, ^rc/i. /. Hygiene, 1900, xxxvii. 290; Tbommsdorp, ibid., 1901, xl. 382. — 114. LowiT. Vorlesungen iib. allgem. Pathologic, Jena, 1897. — 115. BoRDET. Ann. de VI. Pasteur, 1899, xiii. 15 ; 1901, 232; ibid. 303. — 116. Lubarsch. Ctbl. f. Bakt., 1889, vi. 841. — 117. Gbngou. Ann. de VI. P., 1901, xv. 68. — 118. A criticism of the facts bearing upon these experiments is given in Jacoby, M., Immunitat und Disposition, Wiesbaden, 1906, an excellent study of the immunity problem. — 119. Pfeifper. Ztsch. f. Hygiene, Digitized by Microsoft® 246 INFLAMMATION 1894, xvi. 268; ibid., 1896, xviii. 1. — 120. Bobdet. Ann. de I'l. P., 1895, ix. 462. — 121. WRiaHT and Douglas, Proc. B. S., 1903, Ixxii. ; 1904, Ixxiii. 128; 1904, Ixxiv. 147; see also Bulloch and Aticin, ibid., 1905, clxxiv. 379. — 122. Weight and Reid. Proc. B. S., 1906, Ixxvii. 194. — 123. Opie. Journ. of Exp. Merf., 1907, ix.515. — 124. A inlby Walker. Journ. of Pathol, ld02, viii. 34. — 125. Welch. Brit. Med. Journ., 1902, ii. 1105. — 126. Bail. Arch. f. Hygiene, 1905, lii. Hefte Sand 4. — 127. Bulloch. An admirable account of these researches upon Opsonins and Opsonic Treatment is given by Bulloch, Practitioner, 1905, Ixxv. 589, together with full literature to date. A brief but clear account is also given by Ross, G. W., B.M.J., 1906, 2.— 128. Wood HEAD. Bacteria and their Products, London, Scott, 1891. — 129. Pawlow. The Worh of the Digestive Glands, transl. by W. H. Thompson, London, Griffin, 1902, 160; Bayliss and Starling. /o«r?i. o/P/ii/sioJ., 1904, xxx. 61. — 130. Metchnikofp and Delezbnne. C. B. Soc. de Biol, 1902, 282. — 131. Samuel. Lubarsch-Ostertag Ergebnisse, Abt. 1895, ii. 65. — 132. Bieb, A. Die Hyperamie als Heilmittd, 2nd edition, Bonn, 1905. (The second edition is much fuller than the first.) — 133. Ainley Walker. Inflammation, Infection, and Fever, London, Lewis, 1904. — 134. Klotz, 0. Journ. Exp. Med., 1905, vii. No. 6. — 135. Halliburton. Chemical Physiology and Pathology, London, 1891, 340. — 136. Reuss. D. Arch. f. Idin. Med., 1881, xxviii. 317; HoPMANN. Lehrb. d. Zoochemie, Vienna, 1879 ; Virchows Arch., 1879, Ixxviii. 250 ; Mehu. Traitede chimie medicate, 1878, 198 ; Letulle. L' Inflammation, Paris, Masson, 1893, 256. — 137. Miller, J. L. "Transudates and Exudates," Amer. Med., 1904, viii. 835. — 138. Welch. The locus classicus for a description of the process of Thrombosis in our language is Welch, W. JH., article " Thrombosis and Embolism " in AUbutt's System of Medicine, vol. vi. — 139. Neumann. Arch. f. mihr. Anat., 1880, xviii. 130 ; Zieglers Beitr., 1889, v. 345; Virchows Archiv, 1896, cxliv. 201; ibid., 1896, cxlvi. 193. — 140. Marohand. Virchows Archiv, 1896, cxiv. 314 ; Obth. Gottinger Nachrichten, 1896, Heft 3 ; Gtbl f. Path., 1896, vii. 850; Ziegler. Gtbl f Path., 1896, vii. 849. — 141. Gaylord. Journ. of Exp. Med., 1898, iii. 1. Gives literature to date. — -142. Loeb, L. Biological Bull Wood's Hole, 1903, iv. 301 ; see also Lowit. Zieglers Beitr., 1889, v. 469. — 143. Werneckde Aquilar. Inaug. Diss. Tiibingen, 1903. — 144. Adaml Montreal Med. Journ., 1903, xxxii. 401. — 145. Adaml Phila- delphia Med. Journ., 1898, 373. — 146. Salkowskl Virchows Archiv, 1897, oxlvii. 1. — 147. Jagoby. Gtbl f allg. Pathol, 1902, Digitized by Microsoft® EEFERENCES 247 xiii. 2. — 148. Conradi. Bcitr. s. chem. Phys. u. Path., 1901, i. 193. — 149. MuLLEE. aOsfcr Gooigr. f. inn. Med., Wiesbaden, 1902. — 150. Opib. Jouni. of Exp. Med., 1905, vii. 316 ; ihid., 1906, viii. 410, and 1907, ix. 391.— 151. Arnold. Virchows Archil', liv. ; 1872, 1 (Den-lopment of Gapillaries) ; 1873, Iviii. 231 (on Diapededs) ; 1876, Ixvi. 77 (on Cement Substance) ; 1876, Ixviii. 465 (on Lymph- Spaces). — 152. Kolossow. Zeitschr. f. wiss. Mihrosh. ix., Hefte 1 and 3. — 153. Rindfleisch. Pathological Histology. Transl. Baxter. New Syden. Soc, 1872, i. 92. — 154. ZiBGLER. The various editions of his Allgemeine Pathologic give the literature of this discussion up to date. His general articles upon Inflammation {Zieglers Beitr., 1892, xii., and Twentieth Gentury Practice of Medicine, New York, 1899) deserve study. — 155. Wharton Jones. Phil. Trans., 1846, 64. — 156. Lister (Lord). Phil. Trans., 1858, cxlviii. 678. — 157. Weber. Quoted by Lister (156). — 158. Ryneck. Rolletts Untersuchungen, 1870, 103. — -159. Addison, W. Exptl. and Pract. Researches upon Tiiji., London, 1843. W. Addison, who must not be confounded with T. Addison, the celebrated Guy's physician, was the first English hismatologist. He had described the existence of leucocytes in blood in the London Med. Gazette of December 1840 and January 1841. He described blood platelets, their relationship to fibrin formation, and the leucocytosis of inflammation. Vide H. A. M'Callum, Lancet, i., 1907, 182. — 160. Waller, Aug. Phil. Mag., 1846, xxix. 217, 298, 397. — 161. Dutrochbt. Recherches anat. et physiol. sur la structure interne des anim., etc., Paris, 1842, 214. — 162. Martin, Sidney. Lectures on General Path- ology, London and Philadelphia, 1904. — 163. Lavdowsky. Virchows Archiv, 1884, xcvii. 177. — 164. Binz. Virchows Archiv, 1874, lix. 293; ibid., 1878, Ixxiii. 282; ihid., 1882, Ixxxix. 389. — -165. Disselhorst. Virchows Archiv, 1888, cxiii. 108. — 166. Bouchard. " Essai d'une theorie d'infection," Verhandl. d. X. internal, med. Gongr., Berlin, 1890. — 167. Roger. Gontrib. d I' etude de I'immunite' acquise, -p. 1. — 168. Charrin. Verhandl. d. X. internal, med. Gongr., Berlin, 1890, ii. part 3, p. 29. — 169. Buffer. Ann. de I'histit. Pasteur, 1891, v. 673 ; Brit. Med. Journ., 1890, i. 1177. — 170. Sidlbe. Diss., Zurich, 1895. — 171. Mall. Arch. f. Anat. u. Physiol, Physiol. Abt., Suppl. Bd., 1890, 57.— 172. Klbbs. Allg. Pathologic, 1889, ii. 384. — 173, Sbvbrini. La Gontrattilita dei capillari, 1881. — 174. Meltzee and Meltzee. Journ. of Med. Research, 1903, x. 135 ; Am. Journ. of Physiol, 1903, ix. 57. — 175. Gehgens. Pfliigers Archiv, 1876, xiii. 591. — 176. Rutimeyee. Arch, f exptl Pathol, 1882, xiv. Digitized by Microsoft® 248 INFLAMMATION 384. — 177. Samuel. Virchows Archiv, 1890, cxxi. 396. — ^178. Roger. G. B. Soc. de Biol, 1890, 222 and 646.— 179. Head and Campbell. Brain, 1900, xxiii. 3.03.-180. Virchow. Cellular Pathology, Eng. Ed. transl. from 2nd edition by Chance, London and New York, 1879.— 181. See MacCallum, W. G. Johns Hopkins Hasp. Reps., 1902, x. 375 ; Journ. Am. Med. Assoc, Sept. 3, 1904 ; see also Krbtz. Wiener Idin. Wochenschr., 1900, xiii. 271. — 182. Baumgarten. Uher TuberJcel u. Tuberkulose, i. ; JDie Histogenese des Ttiberlculosenprocesses, Berlin, 1885. — 183. Weiuert, C. Gesammelte Abhandl, Levpzig, 1906, i. — 184. Leviu, I. Journ. Med. Research, 1901, vi. 145. — 185. Starling. Oroonian Lectures, Roy. Soc, and Lancet, xx., 1905, ii. — 186. Schbltema. D. nied. Wochenschr., 1887, 463 ; Nikiforoff. Zieglers Beitriige, 1890, viii. 419.-187. Krafft. Zieglers Beitrage, 1., 1884. — 188. PoDM'YSSOZKi. Zieglers Beitrage, 1884, i. — 189. CoEN. Zieglers Beitriige, 1888, ii. 29 and 107. — 190. Fischer. Diss., Tubingen, 1888. — 191. Arnold. Arch. /; mihr. Anat, 1887, xxx. 205.; — 192. Marchand. Zieglers Beitriige, 1888, iv. — 193. Eeinke. Zieglers Beitrage, 1889, v. 439 ; Ziegler, Allgem. Pathologic, lOtli edit, Jena, 1901, 380, gives good bibliography on this subject. — 194. Sherrington and Ballance. Journ. of Physiol, 1889, x. 550; Gtbl f. Pathol, 1890, i. 697. — 195. JfJRGENLUNAS. Zieglers Beitrage, 1901, xxix. 92. — 196. Beattib and Dixon. General Pathology, 1908, 215. — 197. Tadei. La Fibre elastich. nei tessute di cicatrice, Ferrara (A. Soati), 1903 ; Schifpmann. Gtbl f. Path., 1903, xiv. 833 ; Katsurada. Zieglers Beitrage, 1902, xxxi. 296. — 198. Gilchrist. Johns Hoplcins Hosp. Repts., 1896, i. 269; Gilchrist and Stokes. Journ. of Exper. Med., 1898, iii. 53 ; see also Hektoen. Ibid., 1899, iv. 261 ; Eicketts. Jown. of Med. Res., 1901, vi. 374. — 199. Boycb. Journ. of Path., 1893, i. 164 ; see also Grawitz. Virchotvs Archiv, 1880, Ixxxi. 355, and Leber (34). — 200. Nicholls. Studies from the Royal Victoria Hosp., Montreal, 1902, i. No. 3 ; see also Kelly. Am. Journ. Med. Sci, 1903, cxxv. 116. — 201. Martin, E. Montreal Med. Journ., 1896, xxiv. 860. — 202. Adaml "On the Eelation- ship between Inflammation and Sundry Forms of Fibrosis'' (Middleton- Goldsmith Lectures), Med. Record {N.Y.), 1896, 361, 397, 469, 505. — 203. Jobbs, L. Wesen u. Entvnckelung der Arteriosklerose, Wiesbaden, Bergmann, 1903. — 204. Martin, C. F. Trans. Assoc. Am. Phys., 1 905, xx. — 205. Eolleston. Diseases of the Liver, Philadelphia, New York, and London. Saunders, 1905, 175. — 206. Thoma. Virchows Archiv, civ. and subsequent volumes; Zieglers Beitr., 1891, x. — 207. Councilman. Trans. Digitized by Microsoft® EEFEEENCES 249 Assoc. Am. Phys., 1891, vi. 179. — 208. Carrel. Journ. of Exp. Med., 1908, \. 130. — 209. Careel and Guthrie. Siiry. Gyn. and Obstek, 1906, ii. 275. — 210. Koy and Adami. Brit. Med. Journ., 1888, ii. 1321. — 211. Filehne. Proc. Physiol. Soc, Cambridge, 1892 (apparently not published in the Journ. of Physiol, although it is referred to in the Virchoiv-Hirsch. Jahrhuch). — -212. Paste dr. Bull, de I' Acad, de me'd., 1879,1 152. — 2 1 3. Charrin. La Maladie pyocyanique, Paris, 1889. — 214. Roy and Cobbett. See art. "Shock" in 1st edition of AUbutt's System, iii. 326; see also Sherrington and Gopeman. Journ. of Physiol, 1893, xiv. 52 ; Lazarus Barlow. Ibid., 1894, xvi. xiii. — 215. Chile. An Ex- perimental Research into Surgical Shock, Philadelphia. Lippinoott, 1899 ; see also Parascandolo, Arch, de Physiol, 1898, x. 188. — 216. Ribder. Beitrage z. Kenntnis d. Leukocytose, 1892. — 217. Lowit. Arch. f. mikr. Anat., 1891, xxxviii. ; 1890, xxxvii. ; Zieglers Beitrage, 1891, x. ; Studien k. Phys. u. Path, des Bhites, 1892.— 218. Sherrington. Proc. Boy. Soc, 1894, Iv.— 21S). Everard, Uemoor, and Massabt. Ann. de I'Instit. Pasteur, 1893, vii. — 220. Welch. Amer. Journ. of the Med. Sciences, 1897, cxiii. 631. — 221. Rupper. Brit. Med. Journ., 1897, i. 1177. — 222. Nicholls. Joiwn. of Med Research, 1904, xi. 455. — 223. FoBD. Journ. of Hygiene, 1901, i. 277, with series of tables in Trans. Assoc. Am. Phys., 1900, xv. 389, — 224. Wrosczek. Arch, ■polonaises d. Sc. biol. et. med., 1903, ii. 1796 (Ref. Journ. de physiol et path, gen., 1904, vi. 385). — 225. Adaml Journ. Amer. Med. Assoc, Dec. 23, 1899.— 226. Harris, D. F. Brit. Med. Journ., 1900, ii. 741. Digitized by Microsoft® Digitized by Microsoft® INDEX Abscess — metastatic, 48 mode of formation, 42 et scq. Adaptation, 232 et seq. imperfections of, 234 ; in fibrinous inflammation, 140 in amoebiB, 13 in myxomycetes, 9 individual, 235 Aggressins, 116 Alexins, 108, 113 Amboceptor ( = immune body), 123 Amceba, 6 adaptation in, 13 cultivation of, 8 Anti-enzyme, of exudates, 143 Arteriosclerosis, 201 Artery, replacement of, by vein, 204 Astropecten, 14 Auricular nerves, 169 Autolysis, 142 Axolotl, 23 Bacterisemia, 47 Bactericidal substances of serum, 108 Bacteriolysin, 126 Basophil cells, 62. jS'eeaZso Leucocytes, Properties of Bier's treatment, 130, 227 Blood current, slowing of, 37, 118 Blood-vessels. See also Vascular System formation of new, 149 phagocytic activity of endothelium, 76 the part played by them, 146 et seq. Calcareous infiltration or degenera- tion, 179 Capillaries, formation of new, 150 Carrel's experiment, 204 Cellulo-humoral hyjiothesis, 107 etseq. Chemiotaxis, 9 et seq. as an explanation of junction of capillary loops, 150 as cause of diapedesis, 159 as cause of febrile leucooytosis, 225 of leucocytes, 93 physics of, 10 Clasmatocytes, 80 Cohnheim's experiment on frog's web, 36 views regarding inflammation, 146 Complement ( = cytase), 123 Cornea, effects of injury to, 24 Cryptogenic infection, 228, 237 Cytase, 98, 122 Cytolysin, 125 Daphnia, reaction to injury in, 19 Defensive proteids, 108 Definition of inflammation — Burdon-Sanderson, 4 Grawitz, 5 Metchnikofi', 98 Ribbert, 52 primitive (Celsus), 3 summing up of author, 238 Degenerative processes, 174 et seq. due to diffusion of toxines, 52 Diapedesis. See Migration of Leuco- cytes Elastic tissue, its regeneration, 194 Elephantiasis, 202 Endothelium, vascular, self-regulative properties, 167 phagocytic properties, 76 251 Digitized by Microsoft® 252 INFLAMMATION Enzyme action, 122 et seq. Enzymes — of bacteria, 141 of inflammatory exudates, 142 of leucocytes, 142 of tissues, 122 Extracellular activities, 16 in annelid worms, 1 7 Exudate — arresting primary union, 33 enzymes of, 142 librin, 135 et seq. ; its protective effects, 129, 139 in Cohnlieim's experiment, 40 the cells of, 49,> 135 the fluid of the, its properties, 120 et seq. the solids of the, 132 et seq. Ferment action. See "Enzyme Action Fermentator, 124 Ferments. See Enzymes Fever, 51, 225 Fibrin, 135 et seq. Fibroblasts, 44 in granulation tissue, 193 their origin, 185 Fibrosis, 190 et seq. inflammatory, 195 neoplastic, 200 non-inflammatory, 202 productive, 197 replacement, 199 transitional, 200 Fibrous hyperplasia, 190 et seq. Fixateur, 113 Frog- inflammation — of tadpole's tail, 35 ; of web of foot, 36 Geugou's experiment, 110 Giant cells, 87 Gluge's corpuscles, 87 Granulation tissue, 44, 190 Herpes zoster, 170 Humoral hypothesis, 104 et seq. Hyaline cells — as endothelioid leucocytes, 83 identity with macrophages, 75 in peritoneal cavity, 73 originating from vascidar endothe- lium, 71 summary, 188 Hyperfemia, active, distinction from inflammation, 167 induced. Bier's treatment, 227 passive (venous obstruction), 167 Hypnotic production of the inflam- matory process, 171 Immune (= intermediary ) body, 113, 122 et seq. Infection, distinct from inflammation, 53 Inflammation not a general process, 52 Intermediary body. See Immune body Issaeft"s resistance period, 100 Leishman's experiment, 100 Leucocytes — amphophil, properties of, 62 basophil, properties of, 62 clasmatocytes, 80 classification — Wharton Jones, 61 ; Max Schultze, 61 ; Ehrlich, 62 ; Metchnikofl', 63 ; Kanthack and Hardy, 63 ; Durham, 63 ; ac- cording to origin, 64 diapedesis of, 155 et seq. , eosinophil, properties of, 62, 85 forms of— in Daphnia, 19 ; in Astacus, 19 ; in vertebrates, 61 et seq. hiematogenous, 65, 66 histogenous, 65, 72 et seq., 87 histo-hffimatogenous, 66, 66 et seq. hyaline, derived from vascular en- dothelium, 71 ; properties of, 63 lymphocyte, granulations of, 67 ; properties of, 63, 65, 86 mesodermal origin,' 15 neutrophil { = polymorphonuclear) properties of, 63, 86 of epithelial origin, 78 of muscular origin, 79 plasma cell, 67 Leucocytosis, 52 Lubarsch's experiment, 110 Maorooytase, 98, 110 Macrophage, 63, 75 Macroxycyte, 64 Margination of leucocytes, 37 Mast cell, 83, 86 Metastatic abscesses, 48 Metazoa, response to injury in, 14 Digitized by Microsoft® INDEX 253 Microcytase, 98, 110, 113 Micro-organisms in healthy tissues, 236 setting up different varieties of inflammation, 220 Microphage, 63 Microsphsera, 8 Mioroxycyte, 64 Migration of leucocytes, 29, 39, 155 et seq. Mucin, 180 Myxomycetes, 9 Nervons system, part played by, 164 et seq. New vessels — development of — in cornea, 30 ; in wounds of skin, 34 formation of, 149 in healing abscess, 44 Non-vascular areas — axolotl, 23 cornea, 24 newt, 24 Nuttall's experiment, 104 Omentum — in peritoneal inflammations, 140 Opsonins, 114, 131, 227 Oxyphil cells, 63. See also Leuco- cytes, Eosinophil Pfeiffer's phenomenon. 111 Phagocytosis, 89 et seq. by flbroblasts and growing cells, 185 by lymph-endothelial cells, 75 by macrophages, 75 by vascular endothelial cells, 76 in Astropecten, 14 in Ecliinoderms, 14 in Protozoa, 7 Phlebosclerosis, 202 Plasma cells, properties of, 67, 69, 87 Polyblasts, 69 Polymorphonuclear or polynuclear. See Leucocyte, Neutrophil Protozoa, intracellular digestion, 8 response to injury, 6 Purpose in vital phenomena, 234 Pus— in developed abscess, 43 laudable and foul, 191 Ranvier's cells, 87 Referred inflammation, 171, 230 Regeneration, 181 eZ seq. in annelid worms, IS in Hydra, 17 in inflamed web of frog, 40 in primary union, 34 in rabbit, after abscess formation, 44 of corneal corpuscles, 31 Repair. See Regeneration Reserve force, 235 Resistance period, 100 Reversionary metamorphosis, 177 Ribbert's views regarding inflamma- tion, 52 Ryneok's experiment, 153 Samuel's experiment, 132 Schemata — collation of names of leucocytes given by different observers, 64 forms of leucocytes concerned in inflammation, 83 of forms of fibrous hyperplasia, 206 origin and relationship of different forms of leucocytes, 84 proteid contents of exudates and transudates, 134 Septicaemia, 47 Serous cavities, production of sup- purative inflammation in, 49 Stasis, 231, 39 Stigmata and stomata, 148 Summary — of conclusions reached regarding degeneration and regeneration 188 of conclusions reached regarding mode of action of leucocytes, 121 of conclusions reached regarding part played by blood - vessels, 153 ; passage of leucocytes, 163 of conclusions reached regarding part played by the nervous system, 172 of conclusions reached regarding the inflammatory exudate, 144 of data afforded in Part I., 54 of forms of leucocytes, 83 of phagocytosis theory, 96 of process of suppurative inflamma- tion, 45 of properties of different forms of leucocytes, 85 Digitized by Microsoft® 254 INFLAMMATION Summary of relationships of leuco- cytes, 84 Suppuration — by chemical irritants without bacteria, 42 experimental production through bacteria, 42 et seq. Surface tension and chemiotaxis, 11 Sympathetic inflammation, 170 nerves of ear, 169 Systemic changes, 52, 223 et seq. Temperature changes, 207 et seq. Tissue immunization, 226 Treatment, principles of, 227 et seq. Trophic inflammation, 165 Ulceration, exogenous, 140 of web of frog, 41 Varieties of inflammatory manifesta- tion, 213 Vascular areas, experimental produc- tion of inflammation in, 32 et seq. Vascular system, and its relationship to the inflammatory reaction in the lower Metazoa, 18 ; in verte- brates, 22, 36, 56 ; distinction between active hyperjemia and inflammation, 167 Venous obstruction, 167 Virchow's views regarding inflamma- tion, 176 Vital inertia and habit, 237 " Wallbildung," 108 Weber-Fechner law of sensibility, 162 Weigert on cell growth, 183 Wright's phenomenon, 114 Printed by R. & R. Clark, Limited, Edi7iburgh. Digitized by Microsoft® A SYSTEM OF MEDICINE BY MANY WRITERS 8vo. 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