Inflammation and Its Sequels

INFLAMMATION AND ITS SEQUELS. The protean character of inflammation is sufficient explanation of the fact that none of the numerous attempts to define the condition has been entirely successful. The term represents the sum of changes loc ally produced in a living tissue by the action of an irritant, and since the constituents of the tissues and the characters of irritants vary within enormously wide limits, it follows that the phenom ena of inflammation vary within wide limits also. Nevertheless, the four "cardinal signs" indicated by Celsus (A.D. 34) viz., redness, swelling, heat, pain, are in varying degrees present in every case of inflammation, and subsequent centuries only added to these four signs, a fifth, impairment of function.

From a clinical point of view inflammation may be acute, sub acute or chronic, may be widespread or localized, may produce intense destructive changes or little obvious effect, may be rela tively unimportant so far as life is concerned, or may endanger life from the outset. Essentially, however, the phenomena are the same in kind though individually varying in degree to an infinite extent. This is true even if the irritant evoking the inflam mation be one and the same. The micro-organism known as sta phylococcus aureus, lodged in the cardiac valves, produces valvular disease of the heart, with the entire chain of events that valvular disease entails; in the subcutaneous tissues, leads to a pustule; in the liver, to an abscess ; within the skull, to cerebral abscess or meningitis, in the superficial layers of the skin, to a pustular der matitis, to mention but a few examples. Here the different effects depend, in large measure, upon the seat of lodgement of the micro-organisms. Other variations depend upon the specific character of the infecting micro-organism. Lesions produced by B. tuberculosis, Treponema pallidum (syphilis), B. diphtheriae, B. perfringens (gas-gangrene), B. pestis (plague), V. cholerae asiatica, have peculiar characters, so that a cursory examination might fail to discover that essential identity of phenomena which underlies all of them.

Inflammation and Repair.

One of the greatest difficulties in visualizing inflammation lies in the fact that whatever may be the effect of the irritant upon the tissues at the focus of its maxi mum intensity, that focus is surrounded by concentric zones in which the intensity of the irritant action, by degrees, falls off to zero. In correspondence with this the reaction of the tissues shows concentric zones of variations which, in turn, shade off to zero. An example will make this clear. If a needle be raised to a dull red heat and the point be applied momentarily to the skin on the back of the hand, the reaction which ensues will occupy, say, a circle with a diameter of o. cm. In the centre there will be absolute death of certain epidermal cells, around this there will be a blistered zone, in its turn surrounded by a zone of red ness, heat and pain, intense nearest the seat of injury and grad ually shading into the normal skin of the periphery as one passes away from the centre. These phenomena depend upon the in tensity of the heat acting on the tissues in each concentric zone and the effects of heat on the cells, from the centre outwards, are immediate death, injury so severe that recovery is impossible, injury sufficiently slight that recovery is possible, stimulation to increased normal activity. That increase of normal skin activity may follow on exposure to suitable temperatures is shown by the redness and sweating experienced on a summer day.

The peripheral appearances described above do not occur at the moment that the hot needle is applied, but take some time for their production, and disappear in reverse order until the normal condition of the skin is re-established. That is to say, the local inflammation is followed by regeneration and repair. It is this essential association of reparative or stimulative processes with destructive or inflammatory processes that renders study of inflammation so difficult, but the two types of process must be entirely distinct, for stimulation occurs in the normal processes of life in which inflammation is completely absent, though these same stimulative processes are responsible for the regeneration and repair that normally follow inflammation. In a word, in flammation is essentially degenerative and destructive, but of necessity brings regeneration and repair in its train. Recognition of this principle is of fundamental importance in treatment, as it indicates that before repair can take place at a given spot every source of irritation, i.e., of inflammation, must be removed. It is intelligible, too, that a tissue on the way to repair may itself fall under irritant action. Then the phenomena of repair and of inflammation are commingled ; the result is chronic inflammation.

The Inflammatory Process.

A minute injury like that de scribed above, with the vascular and tissue changes it induces, is an epitome of the phenomena of inflammation in general. Microscopical examination shows that in the inflamed area the blood vessels and the tissue elements are modified. The blood vessels are affected differently in the central and peripheral regions. Towards the centre of the area they are dilated and the blood therein is stationary, the red blood corpuscles have lost their individual contours and channels and blood may be repre sented by homogeneous red cylinders. Further out the vessels are dilated also, but the blood flow through them, though retarded, has not ceased, and outside the vessel walls are red corpuscles, polynuclear leucocytes and fluid that have escaped from within the lumen. Still further outwards the vessels are dilated and the rate of blood flow is much increased; this zone gradually merges into the region of normality. The essential cells of the part also share in the reaction, showing modifications varying from com plete disintegration to cloudiness of cytoplasm and disruption of nuclei. Thus in every example of inflammation there are vascular changes associated with dilatation of vessels, modifications in rate of local blood flow, exudation of fluid, emigration of leucocytes, extravasation of red corpuscles, and disorganization of the essential tissue elements. Such differences as are introduced by variations in the type of injury and kind of tissue involved are differences of degree, not of kind. But, primarily, it is the local increase of blood flow that accounts for the "redness" and "heat," the exudation that accounts for the "swelling" and "pain," the tissue changes that account for the "impairment of function." Obviously, with a given injury, where the tissues are normally loose, e.g., skin of back of hand, swelling will be relatively great, and pain relatively slight ; where the tissues are normally tense, e.g., the pulp of the fingers, swelling will be slight and pain great. The lack of distensibility of the teeth, and of the bony sockets of the jaw in which the teeth are set, amply explains the acute pain of toothache.

The phenomena associated with inflammation may be distress ing to the patient, but of temporary importance; on the other hand, they may be so excessive that they constitute in themselves sources of irritation to the tissues in which they occur. A blow in the neighbourhood of the knee may lead to local inflammation, with so much pain and effusion that the joint is kept immobile sufficiently long for atrophy, from disuse, to occur in the muscles moving the joint, and occurrence of adhesions within the joint itself. Hence the primary irritant may be reinforced by secondary and subordinate irritants, and in many instances the latter lead to the greater degree of disability. Other examples of the dom inating influence of these secondary irritants are seen in cases of pleural and pericardial adhesions, ascetic collections of fluid, necrosed bone (sequestra), renal and biliary calculi. In all in stances, however, whether it be by way of primary or of sub ordinate irritants, the tissue elements involved determine the ultimate effects of the inflammation. According as they are nervous, muscular, renal, connective tissue, or of other kind, the features of the symptoms resulting from the inflammatory lesion are determined, and in proportion as the tissue cells themselves are relatively vulnerable and predominate in the affected region, the symptoms are produced by relatively low degrees of irrita tion. Particles of dust that are without effect on the skin or mucous membrane of the mouth may cause profound inflamma tion of the eye; oil of turpentine which, acting on the skin, merely reddens it, when acting on the secreting cells of the kidney, leads to an intense, possibly a fatal, nephritis.

Irritants, Non-organic and Organic.

Hitherto the irritants that have been mentioned may be regarded as non-living or un organized, and such irritants are of the widest variety, chemical, physical, mechanical; the strong acids and alkalies, the poison injected by a bee, wasp, or stinging nettle, heat, cold, ultra-violet and other radiations, bullets, sprains, blows, cuts, are a few examples. There is even some reason for believing that, in hysterical subjects, irritants may be psychological, though all such statements must be received with caution in an individual case. In all the above-mentioned instances the irritant action is momen tary, or at all events, limited, and the inflammation is correspond ingly limited. It reaches its height, and so soon as the primary and consequential subordinate irritants have ceased to be effective, owing to their actual removal, dilution, neutralization, and so forth, the strictly inflammatory processes come to an end and resolution, regeneration and repair (see below) come into play.

But there is another, and in most respects, a far more impor tant variety of irritant that leads to inflammation. The irritant here is living or organized, and the group embraces the whole range of pathogenetic bacteria and animal parasites that affect the solid tissues. The inflammatory phenomena are dominated by the fact that the irritant has the power of living and multiplying within the animal tissues, and though, fundamentally, the tissue reactions towards this type of irritant are identical with those towards non-organized irritants, the scales are weighted from the first in favour of the irritant and against the tissue it invades. To produce a given result a smaller initial injury is sufficient when the irritant is bacterial, because the irritant has in the toxin it produces a weapon that the non-organized irritant has not, has in its power of multiplication a power of escaping from the region where the tissues are opposing it and carrying its injurious action to a distance. And in the course of these activities it occasions such pathological conditions as abscess, ulceration, gangrene, necrosis, sepsis, fever, nervous symptoms; and the train of ill effects extends indefinitely. Whether the patient succeeds in over coming the primary and secondary irritants, and in repairing the damage they have caused, or succumbs under the attack, is determined by the factors influencing his immunity or suscepti bility.

Mode of Operation of Bacterial Irritants.

It follows from what has been said that, theoretically, the entrance of a single pathogenic micro-organism into the tissues is sufficient, and actually the mere prick of an infected needle has in many instances led to severe general illness, sometimes to death. It follows, too, that the sequels of an inflammation caused by an organized (bacterial) irritant are more pronounced, last longer, and induce more damage to the tissues than those following the action of a non-organized irritant of comparable magnitude. This truth lies at the bottom of all antiseptic and aseptic surgery. It also furnishes the main explanation of abscess formation, ulceration, focal necrosis and gangrene, as pathological sequels of inflammation. An abscess, pathologically, is merely a collec tion of dead tissue cells, polymorphonuclear leucocytes and exuded blood plasma which, at first solid, has become liquefied by the proteolytic action of enzymes. That this destruction of tissue cells, migration of leucocytes, exudation of blood plasma, pro teolysis, are on so great a scale that a macroscopic abscess re sults, depends upon the bacterial character of the irritant at work; pathologically, an identical condition, though of micro scopic proportions occurs preparatory to the healing of every perfectly aseptic wound. For in both instances the irritant (bacteria or knife) causes death of tissue cells, vascular changes, passage of leucocytes and plasma from within the blood vessels to the lymph spaces outside, local coagulation of the exuded fluid and its subsequent proteolysis.

Here the danger must be indicated of considering inflammation as Merely a local proret"s, one at times affecting a large: area. (;ranted that the local phenomena. attract most attentiorn yet it is clear that the increased local blood flew can only carried out by a re-arrangement of the e:ires,il.ation over the v body, that the exuded fluid implies a general re-arrasigtrr. = - • '. the intro- and extra-vase: War relations, that the localized of leue.,ucytes, often in huge numbers, a redistribution of their numbers within) the care ulatin,g blood, and of ten an inc teased out at t he seats; of t}:= - normal production. The experimental evils - (Jr the zt ssits lies in the altered specific gravity blood and of tissues at distant parts of the body, arid the altered corpubc. ular ((institution of the blood (particularly concerning the n u rr, be'J r,1 !J(Jlysudcear lforncytet) that accompany local inflam mation. iron. _) too, fever, general discomfort, disordered digestion, altered tor: : vtitirm (A the urine are often other indications that the entir=- )',r)y shares in the change,, finally, the production of pe anti-substance?, to antagonize bacterial irritants is a f un= t J',' of the tissues (see bA( J1 k3A AND and J;uch ant . `; .,t.a iced a r = ' ')n veyed by the blood to the region where they t r. • • [ , at the focus of inflammation.

sequels of inflammation ;,re (a) physiological and

(1i) path'Jlogiea1 '1 o the car ref el' ,. ha been made- repeatedly in the previous section, and it has appeared that they depend upon persistence of irritant action, whether primary or secondary. These pathological sequels dry not call for f urther remark here. The physiological seas gels are those whi eh bring about a restora tion of the iria`iariir.?i part to a healthy condition. In some cases this ray consist in a return to the normal, but in the majority the tissue is not exactly the saint as it was before be(orning irJ fiarried, and often the original tissue is finally replaced by tissue of suite a differ= ' +. kind. The processes at work are termed revolution, rr:ge.' t.i(Jn and repair.

Resolution.--By this is

meant that the processes indicated by 1:s irritant, on the cessation of its action; return) to norrrra.J Jn t r,=. revere order to that in which they were called forth. The c!aS!staI example of resolution occurs in acute lobar pneurnonia caused by M. lint 1f ere the irritarit leads to acute eon cc ttidn of a large: part of the lung, and the dilated blood-vessels pour into the air alveoli inflammatory whir.h coagulates and renders thee affer.ted part of the lung airless, sold and more than when normal. {treat numbers of ;,rJiyf,uelear le-wocyte.s also pass from the blood-ve::seLs and are entangled in the: coaguJurn, 'her with small n endothelial cells from the walls of t r .. air alveoli. Jri an un'_'.'rJplicat' d the irritant action of t}. cuss now eornes to an end because the body has e-labor-. • s the rree.c'A,ary mti-•ubstaiesYS. The (maguJas.'d exudation is liquefier] by pr(Jteolytic enzymes supplied by the p.J yr _ sr Jeucoeytes and the resulting fluid, with any (lead and , rye-11s is removed fry expectoration, drain •' ' t r the e r r e- r „;? by ?.?_•? ? ,rJ, , lr1 0 h - fJl J J j-btrtarti. The or rr r'at r,, r,= , , is re-established, defects in en r.'.• are re''` =.'Jr':ri by division of neighbouring MISS, the airways are reopened and the lung returns to a condi tion that ' • be distinguished head from the normal. in this ce'• •s_ = though the rule: in lobar pneumonia., is the rz' in "., r irr'Aances, thrJugh joints afier_tecj with acute rkorli r P:rr, may also ret ejrn to the normal. Even when the part sappar= .sly return; to normal, rnicro crfpir, exaarninatior, .;bows that this i . af,s>ol u the ease, i.`., that not_ resolution alone, but r= also has played a part in the recovery.

F' (-generation, -The

re-formation of tissue in invertebrates is of ten r r),, : _ ., though a considerable rr,_a.s,% has been +; •, fiver] ; • }i as the crab or lobster will re-f orrn an se vertebrates tur.l'J regeneration is mush issis •' tbocjnr arnjrhilnan like: the tadpole or (newt will re-form a r ', ;doe fail if it has been re-rnoved. In higher veete. brates organ. r= Arts regenerated. it is true that if a portion Of liver tisiaw' r:=', re;rj experimentally, the surrounding hepatic cells (livid, r :a tissue having certain rewcLlanee) to liver tisrv= :end probably r-xercisirig hepatic f maiior, some degree the baTT t, i- perhaps true of renal true. The stimulus (i3 ear. J'J ucf e iive pregnancy, too, leads to a regeneration of uterine nJ ubc ular, and probably also of mammary, secreting systems. But in the latter examples the meaning of regeneration is strained, 'j it is undoubted fact that when uterus or breast has been = inflammatory, as distinguished from physiological..,her organ has been incised for surgical pur ` def is not filled by muscular or glandular tissue. but by bear ti": '.it, i.e., regeneration does rJ rj' but repair. Strictly speaking, in higher vertebrates res= - r.sn to fill an art firiaJ defect is confined to cells of the ep. endothelial arid connective tissue systems arid to In all other systems a defect resulting from irri 7.is n is repaired ; the faulty tissue is not regenerated.

The

re-gee1erati(ir, of epithelium implies that certain cells of a like kind persist in the neighbourhood of the defect, and by their repeated division are able I o re-construct the tissue. Physiolog ically an example (A this occurs in the monthly reeon s t ruction of the tubular glands of the normal endurletnurn. The bases of these glands reach into the muscular wall of the uterus, and per sist when the endornetrium., with the greater part of the glatrth, is cast off in menstruation; it is from, these remnants that the entire glands are re-corrstructed. When a de e' '.curs in the superficial hquawaous epithebutg., e. s'., at the seat of an ulcer, the intact epithelial cells at the periphery arid in time cover the denuded space, At the free edge the cells a- e but one layer thick, but they boon begin- to divide parallel to the surface, until the ere ' skin is stratified and several layers thick This regenera tive property of Square ous epith _ is utilized in the surgical operation kriown as Tierse h gra: .. '''here a large superfi area is, devoid of skin, small grafts are cut from normal reaching down to and including the germinal layer (see TLL. f ) and are applied to the granulating surface. Her. when a gr. has "taken," it f omit a centre for centrifugal g7 of epith= ..:: r1. In this way the covering-in of a large ar= left by a superficial burn, for example, is materially shortened.. The specialized elements of the true skin and subcutaneous tissue, i.e., papillae touch corpuscles arid other sensory organs, sweat glands, sebaceous glands, hair follicles, are not regenerated. Columnar and spheroidal epithelial cells also regenerate provided that cor responding cells persist from which regeneration can take place. When such cells line gland systems the composite system may or may not be regenerated. If the system be simple, e.g., a tubular gland lined by columnar e'JS FIi-uetJ, it will probably be re-formed; if compound, e.g„ a race:- ri lined by spheroidal epithelium, it will probably not be re-f ore The regeneration of occurs in one plane only, and it is doubtful whether fibrous tissue cells d-r, not at times replace them in respect of their tegurr,ent any f unction.. The chief re generative function of endothelial cells is represented in the new formation of blood-vessels. whereby the nutrition of the young tissue being formed to fill the defect is carried out. These new blood-vessels arise from pre-existing capillaries by the local formation of a solid endothelial bud, whi_r_h grows towards the free surface of the wound and gradually becomes canalized. When two such buds from contiguous capillaries have nearly reached the free surface they bend over, their tips rrle°et, fuse and are canalized; hence the two original capillaries are now connected by a newly-formed capillary loop. The tips of these loops can be seen with the naked eye on the floor of a healing ulcer as minute projecting bright red point or "granulations" that bleed on the slightest rough treatment. Should one of the capillaries ultimately become converted into an arteriole or venule the additional coats are formed by extensions from the r_orresprnding coats of pre-existing vessels. This new formation of blood vessels is known as vaicularization, and the tissue in which the new capillary loops occur is known as granulation tissue.

Regeneration of members of the connective tissue group is

one of the most widespread processes following on inflammation. It accounts for the formation of star tissue in repair of a defect, for the production of adhesions in serous cavities, for the repair of bones after fracture. It also accounts for the increase of fibrous tissue in conditions like chronic fibrosis of kidney ("gran ular kidney") and liver (cirrhosis) and sclerosis of bone, though the association of such increased fibrous or bony formation, with an antecedent inflammation is doubtful in some cases. The chief tissues thus regenerated are fibrous tissue with its variants, fatty and mucoid tissue, neuroglia and bone. In all instances the new tissue is formed from pre-existing cells, fibroblasts in the case of fibrous tissue, neuroglia cells in the case of neuroglia, periosteal and endosteal osteogenetic cells in the case of bone. Cartilage both yellow elastic and white hyaline, is regenerated with far less frequency, especially the former variety; their place when de stroyed is usually taken by white fibrous tissue. When regener ated the new material is formed from pre-existing remnants of cartilage, but there is reason to believe that in some cases of bone regeneration a cartilaginous stage is interposed between the fibrous and osseous stages, as in the normal formation of bone through cartilage. Usually, however, repair of bone takes place by direct calcification and ossification without the interposition of a carti laginous stage, thus resembling so-called membranous bone forma tion. In all essential details the newly-formed fibrous tissue or bone resembles the normal tissue, but often it ends by being denser and less regular in its general arrangement. Corresponding with this, cells are more scanty and the inter-cellular substance more pronounced. Calcium salts may be deposited in fibrous tissue formed as a sequel to inflammation, as in the calcareous nodules occurring in pleuritic or pericardial adhesions, or it may become the seat of overgrowth reminiscent of tumour formation (keloid) . In all cases the amount of fibrous tissue formed after inflammation is excessive, at least at first, but for some reason that is not fully clear, inflammatory fibrosis reacts readily to X-radiation, so that redundancy is often treated successfully by this means.

In the case of nerves, the term regeneration is of ten used, but the return of function which may be observed after the severed ends of a nerve have been sutured, is not regeneration in the strict sense. In all the instances described above, regeneration of tissue depends upon re-formation of cells by division of pre-existing cells, but nerve cells once destroyed are never re-formed, and the return of function depends merely upon centrifugal growth of the axis cylinder from the still intact nerve cell along the scaffolding provided by the anatomical nerve, whose continuity has been restored by suture. Experiments that have been regarded by their authors as indicating that the functional nerve is restored by longitudinal apposition of proliferated neuroglial cells, do not carry conviction.

Repair.

The phenomena described above play varying parts in the production of repair, so that the interaction of inflammation and repair and the essential similarity of processes in clinically dissimilar conditions can best be brought out by tracing them in a few illustrative cases.

(I) An Aseptic Surgical W ound.—The irritant here is the knife, and subordinate irritants are reduced to a minimum, probably being represented by the stitches, a small number of tissue cells on the cut surfaces that are injured beyond recovery, and small amounts of blood clot. As the result of these local dilatation of vessels occurs, exudation is poured out in the superficial layers of the opposed cut surfaces, and between them and by coagula tion, temporarily binds them together. Polynuclear leucocytes migrate from the blood stream and by phagocytosis (q.v.) remove dead tissue and remnants of blood clot, and later the fibrin fila ments of the coagulum. At the same time newly-formed capil laries bridge the gap between the two cut surfaces, travelling along the fibrin filaments in the intervening coagulum. Fibroblasts, derived from pre-existing connective tissue corpuscles, range them selves along the new capillaries and build up fibrous tissue whereby the two opposed surfaces are definitely united. On the surface, squamous epithelial cells divide and fill the skin defect and healing is complete. As the newly-formed fibrous tissue grows older it contracts and obliterates the majority of the newly-formed capil laries, so that the scar tissue, which at first was red and excessive, becomes dead-white and contracted.

(2) Fracture of a Long Bone.—(a) the fracture is simple and aseptic. Here the irritant is the force that leads to the fracture, and subordinate irritants, consisting of effused blood from rup tured blood-vessels, torn muscles and ligaments, ruptured medulla of bone, play an important part in respect of their volume, while movement between the fractured ends of the bone may further enhance these. Nevertheless, coagulation of the effused blood oc curs about the ends of the bones and holds them together as a preliminary. The essential difference between the processes here and those obtaining in an aseptic surgical wound consists in the greater mass of material that has to be removed, the greater space that has to be bridged by newly-formed capillaries, the greater distance the migrated polynuclear cells have to travel, and the fact that the endosteum and periosteum, with their osteogenetic cells, are involved instead of white fibrous tissue. In time the blood coagulum around, between and within the fractured ends of the bones, is replaced by a mass of soft bone (temporary callus) derived from periosteum and endosteum, and of this the greater portion is ultimately removed by osteoclastic (i.e., phagocytic) action, while between the fractured ends there remains newly f ormed bone that becomes denser and unites the fracture (defini tive callus). Where the fractured ends are widely separated bony new formation may be impossible and the ends are united, if at all, by fibrous tissue: (b) the fracture is compound and septic. Here the irritant action is increased by the presence of pathogene tic bacteria and their toxins in damaged, dying and dead material resulting from the fracture itself. The pathological sequels of in flammation, suppuration and necrosis, are therefore superposed upon the already important secondary irritants occasioned by the fracture. Even assuming that the bacterial infection does not become generalized and lead to septicaemia or pyaemia (see SEPsis) the original amount of damage to tissues will be in creased by that amount, which is due to the bacterial action as such. When and if these potent adjuvants of the original irritant action have been overcome, and only at those spots at which this occurs, do strictly reparative processes take place, but they are identical with those occurring in an aseptic fracture. In other words, the first object of the body is to render the condition aseptic, and this object the surgeon copies in his treatment of every compound fracture. It can be understood that whereas the healing of an aseptic surgical wound with surfaces well apposed is a matter of days, the healing of a simple, aseptic fracture of bone is a matter of weeks, and the healing of a compound, septic frac ture is one of months.

(3) A Focus of Pulmonary Tuberculosis.—Here the primary irritant is B. tuberculosis, and an apparent difference from the processes summarized above lies in the facts that the reaction of the lung tissue to the bacillus is cellular only, and contains so called giant cells, and that blood vessels are absent from the minute nodule or tubercle. The caseation so characteristic of tuberculosis is dependent upon these differences (see TvBERCU which are correlated with the relative chronicity of the process. But the tubercle when formed, besides replacing a certain amount of lung tissue, is a foreign body, and as such leads to in flammation in the surrounding tissues, often with a degree of con gestion that explains the haemoptysis that may accompany early tuberculosis. If it be situated on the surface of the lung the tubercle induces inflammation of the pleura, local death of endothelial cells, and subsequently the production of fibrous tissue in the form of a pleural adhesion. Within the lung itself the tubercle, after undergoing caseation and, perhaps, calcifica tion, becomes surrounded by fibrous tissue in the same way, and by the same local proliferation of fibroblasts, that a fibrous capsule is formed around an aseptic bullet lodged in the tissues. Should the tubercles be numerous and uncomplicated the result ing fibrosis may be irregular and extensive, and should the lesion be complicated by access of pyogenetic micro-organisms, suppu ration and the formation of a phthisical abscess cavity (vomica) are super-added. But even in the latter case, if the primary and subordinate irritants be overcome, the defect of lung is repaired by newly-formed fibrous tissue, which is as surely scar tissue as in any of the other instances that have been adduced.

(4) An Abscess and an Ulcer.—These two conditions are bracketed because an ulcer may be regarded as an abscess from which part of the wall restraining the pus is wanting. Hence the pus produced on the floor of an ulcer drains away as it is formed, whereas in the abscess it accumulates within the abscess cavity. Microscopically, however, the floor of an ulcer and the wall of an abscess are composed of the same elements arranged in the same fashion. When the bacterial irritant has become lodged within a tissue, and has multiplied sufficiently and produced enough toxin to destroy the neighbouring tissue cells, by the or dinary processes of inflammation it produces a hard, hot, painful swelling which consists of coagulated exudation, numbers of poly nuclear leucocytes, dead tissue cells, and living and dead bacteria, the central part becoming liquefied later by proteolytic action and constituting the pus. This focus of inflammation is sur rounded, as has been said earlier, by a zone in which the irritant action has fallen off in intensity to a level at which it ceases to be an irritant and becomes a stimulus. At some less or greater distance from the focus of inflammation, therefore, the necessary factors for the formation of new capillary blood vessels, the pro liferation of connective tissue cells and the production of young fibrous tissue, i.e., the formation of granulation tissue, are present. Obeying hydrostatic laws, the pus within the abscess "points," and by destruction of superficial layers of tissue, ultimately escapes. Relieved of this subordinate source of irritation the wall of the abscess contracts, and the reparative fibrous tissue con stituting the wall goes on to the formation of definite scar tissue instead of breaking down to swell the contents of the abscess. It is at this stage that the abscess and ulcer are identical in com position. In both instances the most superficial layers of the granulation tissue break down into pus, which drains away, and the final healing only takes place when the surrounding epithelium (or in the case of an abscess in an internal organ covered by serous membrane, the endothelium) has regenerated a covering for the newly-formed scar tissue, and has thereby eliminated the possibility of bacterial irritant action.

By application of the principles outlined above a rational ex planation of most examples of inflammation and the phenomena associated therewith can be obtained. Naturally, factors arise that are difficult, even impossible in our present state of knowledge, to explain. One of these is the relation of irritative to stimulative action. According to some authorities, the repair that follows in flammation is initiated by hormones produced by the injured tissues. They see in the formative processes following inflamma tion something akin to the processes which, under other conditions, lead to the production of neoplastic tumours. (W. S. L.-B.)