Pathogenesis

Pathogenesis. Contents: General characteristics of pathogenetic mechanisms and their origin......... 96 Significance of pathogenesis data for therapy and prevention ................... 98 The problem of 'local and general' and pathogenesis .... 99 Significance of correlations in pathogenesis.......Ш Most important mechanisms of development of pathological processes and diseases...................юа Role of substrate in pathogenesis............ П1 Pathogenesis (from Greek pathos-suffering and genesis-origin), a branch of pathology that deals with the mechanisms of development of both individual pathological processes and diseases as a whole. Questions of P. represent a theoretically important, integral part of general and specific pathology, since in each process and each disease we ask how this process or the entire disease developed and arose. For example, in relation to typhoid fever, P. implies questions: where does the disease-causing agent penetrate the body, how does the disease itself occur, for example, damage to the intestines, lymph glands, mesentery, how do Ebert's bacilli enter the gallbladder, what pathogenetic significance does this have in turn, etc. In relation to P. of lobar pneumonia, questions are raised: how do pneumococci enter the lungs (hematogenously, aerogenously, lymphogenously), how does the infection spread through the lung and why is lobar pneumonia usually lobar in volume, what are the relationships between the local (pulmonary) process and the whole organism, how to specifically connect, for example, a cold factor, chest trauma or surgery with the occurrence of pneumonia, etc. As for the relationship between the concepts of P. and etiology, it comes down to the fact that P. answers the question of how the disease develops, while etiology (see) answers the question of why this disease arises, what its cause is. It must be admitted that questions of P. have been studied far from fully. A significant part of diseases, individual processes and symptoms remains pathogenetically unexplained. This is explained by the extreme complexity and multifaceted nature of the P. problem itself and, above all, by the complexity of its connections with other, no less difficult problems of pathology. It is clear, first of all, that the P. problem, on the one hand, closely adjoins the problem of etiology. On the other hand, it is inseparable from clinical medicine, which provides theoretical justification for the course of the disease, its symptomatology, and often guidance for practical actions. Finally, being the theoretical core in the study of the entire dynamics of pathological processes, including their morphology, i.e., pathological anatomy, the problems of P. are inseparable from the fundamental problems of physiology. One cannot, for example, form an understanding of edema without clarifying the physiological basis of water and salt metabolism, in particular those laws that regulate the normal processes of tissue fluid circulation, hydrophilicity of colloids, etc. In other words, pathogenetic regularities cannot be separated from physiological regularities. And since pathological-physiological systems at the same time represent certain differences in different animal species, it is quite obvious that their pathogenetic mechanisms, and consequently the manifestations of corresponding diseases under the same etiological factors, will be more or less different. What has been said applies to an even greater extent to the formulation of the P. problem in humans as social animals. It is completely clear that in the historical development of man, depending on changing conditions of labor and social relationships, as well as in connection with man's impact on the surrounding nature and the continuous change of external factors acting on him, the conditions for the development of diseases and pathological processes changed, and consequently P. also changed. Unfortunately, paleopathology gives us so few (and moreover extremely fragmentary) data about the nature of diseases in primitive man that it is impossible to establish any regularities in the historical development of P. On the other hand, one must consider it indisputable that the change under the influence of changing social conditions of neuropsychic factors, so important for P. (see below), had no small importance in changing the type of pathogenetic processes, and sometimes the nature and course of diseases. It is also easy to imagine that new living conditions can lead to the complete elimination of some old diseases, and on the other hand, they can lead to the creation of new pathological forms while maintaining the same etiological factors. An example of such a modification of pathological forms can be varioloid, which is apparently nothing other than a variety of true smallpox in the vaccinated; this also includes the negative, reverse side of the same vaccination - the occurrence of post-vaccinal encephalitis of our time, which did not exist before the discovery of Jenner. The disappearance of chlorosis from the practice of modern clinical medicine cannot be assessed otherwise than as a result of man's impact on his own nature. Thus, if modern pathology and nosology in content differ somewhat from pathology of long past years and centuries, this is explained, of course, not only by the greater study of what has long existed, but also by the actual evolution of pathological forms and processes. Social factors give the P. problem a specificity that allows one to single out the question of human pathology and new pathogenetic regularities peculiar only to humans. It is indisputable, for example, that elements of consciousness, as well as the entire psycho-physiological structure of a person's personality, reflecting in itself moments of social existence (labor, upbringing, class affiliation, etc.), give a specific uniqueness to the entire P. problem in humans, making it fundamentally different compared to the same problem in animals. All types of qualitative and quantitative starvation, in particular avitaminoses, various intoxications, for example alcoholism, unbearable and exhausting labor, unsanitary conditions of labor and living - in short, all that is characteristic of the living conditions of the deprived classes of capitalist society - is a factor of the greatest not only etiological but also pathogenetic significance. What has been said makes it understandable why data from human pathology can only be compared with data from animal pathology with great caution, for example, when setting a particular experiment. On the other hand, it would be completely wrong to think that these data are generally not comparable: social, despite its enormous role, does not destroy the importance of biological as the greatest factor in P. of disease. General characteristics of pathogenetic mechanisms and their origin. Pathogenetic mechanisms lie within the physiological systems of the organism. The process of the emergence of new pathogenetic mechanisms can itself be designated as a pathogenetic process. For example, by periodically sensitizing an animal to some protein and even bringing the sensitivity to this protein in this animal to the highest levels, we still do not create a disease in it in the clinical-anatomical understanding, but create only the most important prerequisite for such in the form of new cellular and humoral connections, new reactive abilities based on old physiological ones; these new abilities (resp. mechanisms) arose throughout the sensitization. By causing in the same animal the phenomenon of local or general anaphylaxis, we realize these newly emerged mechanisms. Hence the conclusion: the existence of pathogenetic mechanisms should be distinguished from the presence of pathological processes; these mechanisms contain only the possibility of pathological, so-called readiness for it. From the same point of view, one should approach the concept of 'immunity'. Immunity is the impossibility of the occurrence of something. From the point of view of the doctrine of P., this impossibility should be represented as the impossibility of the realization of a certain pathological phenomenon due to the absence of the necessary prerequisites for such a realization; the absence of prerequisites is nothing other than the inactive state of the corresponding pathogenetic mechanisms or, conversely, the presence of the function of such mechanisms that exclude the possibility of the development of suffering. This or that state of mechanisms determining immunity could be given or not given genotypically (natural immunity), it could be paratypic (acquired immunity). The latter category of cases represents a special interest; it teaches that mechanisms preceding the development of a given suffering and realized in it cannot in principle remain the same after the end of the disease. Recovery is not only the end of the disease but also the emergence of a new physiological state, and consequently new pathogenetic possibilities. P. is movement, development; however, it is erroneous to represent this movement simply as a chain, the links of which are sequentially switching on new mechanisms; P. from the very beginning is the movement of a whole series of mechanisms, a branched and at the same time mutually coordinated system, continuously complicating as it branches, i.e., in the course of the disease.

On the other hand, there is no need to conceive of P. as chaos and chance. If, therefore, in studying this or that disease, we simply list the mechanisms of its development, we will, of course, create a chaos of phenomena; but if in the same list we determine the basic, leading link, then the entire P. will without particular difficulty present itself to us as a regular system of movement. Detection of this leading link is the central task of the pathologist; it gives us the key to understanding the essence of this disease. The necessity of accepting a system of complexly branched P. is also dictated by the history of the question. The tendency (not completely extinct even in our time) is well-known for each infectious and even simply febrile disease, since this disease differs from others in some way, to seek a specific causative agent. The best optical means of recent years could not, however, accomplish more than did the optics of the recent past; and this is by no means accidental: the matter lies not only in the causative agent but also in the peculiarities of the macroorganism (e.g., completely different forms of tuberculosis from the same tubercle bacillus). The significance of pathogenesis data for therapy and prevention. It was indicated above that the mechanisms of disease development are derivatives of one or another system of the organism. Since the latter cannot be studied in isolation from the surrounding external factors, it is completely obvious that the indicated mechanisms are not free from the influence of these factors, that by external influence on these mechanisms one can also influence the entire chain of factors which we recognize as necessary for the realization of the disease. From this follows a practically important problem: studying the mechanics of disease development, we must at the same time strive to study those methods of influence with the help of which one can, even despite the presence of an etiological factor, either prevent the realization of the disease as a whole or give it a rudimentary character which is associated only with a minimal threat to the life and health of the subject. This problem has been posed and is already partially resolved by practical medicine. All methods of preventive vaccinations, vaccination, more or less intensively affecting the physiological systems of the organism, modifying the reactions of these systems in immunobiological and physicochemical respects, are in essence attempts of this kind. This also includes methods of pharmacotherapeutic, proteintherapeutic, dietotherapeutic, and partly radiotherapeutic influence. From the same point of view, many, e.g., surgical measures must be considered, such as: attempts to influence angina pectoris by excising certain segments of the sympathetic nervous system, to improve blood supply to the extremity in so-called spontaneous gangrene by denervation of the vascular trunks. Also included here are attempts at intervention in endocrine diseases in the form of removal of certain glands, e.g., epiphyseal bodies and their adenomas in certain bone diseases, goiter in Basedow's disease, etc., on the assumption that the leading pathogenetic mechanism is changes in one or another gland. Intervention in pathogenic mechanisms are also such simple measures as cupping and leech applications, cauterization of the covering tissues, pursuing the goals of changing blood circulation in the pathological focus, to influence a certain reflex arc, etc. It is true, practical medicine has a clear understanding that its efforts directed at certain links in the chain of pathogenetic factors are still rather modest in their success, there is still much crude empiricism here, but this is explained mainly by the objective difficulties of the problem of P itself. Modern pathology clearly realizes that the problem of diseases and the struggle against them is not only an etiological problem, that it is necessary to study not only the causes of diseases but also all the paths leading to the realization of these diseases, that prevention and treatment of diseases can be carried out quite fully only with consideration of pathogenetic factors. Preventive medicine, it would seem, directs the thrust of its measures exclusively against etiological factors, but if, on the other hand, one takes into account the significance of these measures in terms of their effect on the entire organism, it is not difficult to be convinced that these preventive measures to a considerable extent also concern pathogenetic factors, affecting in particular, for example, the state of nutrition, metabolism, on the vegetative system and thereby creating completely new conditions important from the pathogenetic point of view. Hence the conclusion-preventive medicine, carrying out methods of mass measures, directs the latter both toward etiology and toward pathogenesis. It would be incorrect to narrow the tasks of preventive medicine to the field of etiology. The problem of 'local and general' and pathogenesis. Closely connected with P. is the problem of localization of diseases (see), as well as the problem of the relationship between local and general. Pathology and clinical medicine do not know absolutely local processes in the living organism; in all cases of the existence of local processes, they presuppose the presence of certain general factors which either have a productive significance in relation to this local process or successively imprint a certain mark on it, even if this local process arises independently of the general, for example in trauma. Every local pathological process in its expression and development to a considerable degree reflects in itself the general state of the organism (see Inflammation). This methodological premise has long found reflection in clinical practice. Surgeons, e.g., pose the problem of treating wounds and even tumors by special diet, changing the active reaction of tissues and metabolism in them; when seeing furuncles and carbuncles, the clinician is concerned with the examination of urine for the discovery of sugar in the urine. When seeing a so-called septic wound, the physician reasons not only about the causal connection of phenomena in the direction from the wound to sepsis, i.e., from local to general, but also in reverse-about the course of the wound under the new conditions that have arisen in sepsis; these new conditions, as is known, essentially change both the general appearance of the wound ('septic wound') and its treatment. A long-healed and already encapsulated primary tuberculous affection in a child is in this state seemingly a purely local, isolated focus, and nevertheless, since this focus contains live bacilli, it can under certain conditions become a source of severe generalization of the suffering even in advanced age. This phenomenon can be understood only in the plane that in the organism the existence of 'local' and 'isolated' is extremely relative, that the very 'isolation,' on the one hand, is unthinkable without general factors (isolation of the tuberculous focus against the background of developing immunity), and on the other hand, once arisen isolation can be only a stage on the path to the general depending on the same factors. Thus, there is no local without general: the course, outcome, and often even the very origin of 'local' are a function not only of local but also of general. The art of the clinician consists in revealing this interaction in each specific case; and by revealing this interaction, we specify the P. of phenomena, which in turn becomes a guide to action for us. Every so-called general disease, whatever its essence, is revealed to us in one or another phenomenon, resp. symptom, of a local nature. If we say that septicemia is an infectious disease devoid of definite localization, then, without speaking of the fact that this definition is not entirely precise from the anatomical side, it is also imprecise in the sense that the absence of localization here must be understood as the universality of localization. The Arthus phenomenon is a local phenomenon, but to an even greater degree it is a sign of the general, since any part of the skin can be the site of development of this phenomenon. Thrombosis, hemorrhage, necrosis, inflammation-local processes, but our understanding of them and practical guidance in relation to them we derive only by taking into account the general, i.e., the connections with the latter (thrombophilia, hemophilia, increased sensitivity, etc.). It is important, when speaking of the general, not to confuse the concept of the general as the entire organism with the concept of the whole as complex and at the same time local. A tumor, e.g., is a local process (conditionally, of course), but in it, as in a whole, one can and must see particulars. These particulars, such as necroses, hemorrhages, we first of all study in the aspect of the whole, i.e., of the tumor, just as we study the entire tumor in the aspect of the general, i.e., of the entire organism. In other words, not every local must be directly subordinated to the general; it can be a certain particularity, a detail of the local, often very characteristic. Foci of necrosis, e.g., in a malignant tumor are particulars in the local, but we will not understand the local if we detach this particularity from the process as a whole-the indicated necrosis is a necessary link in the development of the local. Thus, every local process obliges us to discover in it a connection with the general, i.e., with the organism. On the other hand, in the same local process it is necessary to uncover the internal regularities contained in the particulars of this process.

Having abandoned purely local concepts, modern pathology has also almost completely abandoned purely organopathological concepts, since the concept of a diseased organ does not denote something organ-isolated. No one any longer considers atherosclerosis a disease only of the arterial system, cirrhosis of the liver a disease only of the liver, nephritis, nephrosis diseases of the kidneys, etc. Everywhere a connection is assumed and usually without particular difficulty proven between organ suffering and the entire organism or with its individual systems. How this connection is realized in each specific case, why for example fibro-dystrophic processes in the bones are combined with adenoma of the parathyroid gland and usually only in one of them, why lenticular degeneration is combined in Wilson's disease with cirrhosis of the liver, tuberous sclerosis of the brain with rhabdomyoma of the heart, etc.—there is as yet no answer to all these questions, and primarily because we are poorly acquainted with the physiological bases of correlative phenomena in the organism, that these bases are only just outlined, for example in the doctrine of the reticulo-endothelial system, in the doctrine of the synergy and antagonism of endocrine glands, in the discovery of the connecting role and trophic influences from the sympathetic nervous system, etc. (see also Skin diseases—The problem of the general and local in the pathogenesis of skin diseases). The significance of correlations in pathogenesis. The question of the correlation of pathological processes is essentially the question of the connection of these processes, of the inevitability, regularity of such connection under certain conditions. In the simplest cases this regularity consists in the sequential unfolding or development of one pathological process from another, when an action, arising according to a cause known to us, itself becomes the cause of a new action and so on. We cannot imagine a thrombus without its subsequent organization, inflammation without regeneration, etc. Correlativity however consists not only in the regularity of the development of one process from another—and within the limits of one and the same process one can see various stages of its development. Such an阶段性, resp. regularity, in the change of phenomena can be observed for example in the formation of an inflammatory infiltrate, it can also be seen in the change of vascular phenomena in inflammation (acceleration, slowing of the current, marginal stasis) etc. This does not of course mean that every necrosis, thrombosis, inflammation etc. always entails the same degree, the same quality of subsequent phenomena: the reaction to necrosis, the processes of organization of a thrombus, regeneration following inflammation etc. can be expressed extremely differently and precisely because the mechanisms of development of each new process can possess their own regularities. If we note for example poor healing of a wound or ulcer, we thereby mark a violation of the correlation of pathological phenomena known to us, since the regenerative process that has come to replace the inflammatory one also has its own conditions of development, being for example a reflection of the general reactive abilities of the organism. It would however be a mistake if in the analysis of phenomena we left without attention the etiological factor itself: the healing of ulcers from x-ray burns is not sluggish because that is a peculiarity of the regenerative processes of the subject, but primarily because this peculiarity of action on the tissue is a property of radiant energy itself and of the initial process which was conditioned by it. Clinical practice well knows how often this or that elementary mechanism proves to be either switched off or so changed that the entire course of the local process is distorted. Essentially the entire question of the so-called complications of disease, of atypical forms of disease presents nothing other than the question of the violation of the usual correlations of elementary processes entering into this or that chain of events. The experience of the clinician and pathologist establishes for all pathological phenomena a certain norm of their behavior in the sense of regular sequence and conditioning. This sequence of phenomena allows one to foresee the future of the entire phenomenon, forming the basis of what we call prognosis. All deviations from the indicated norm of development presuppose the inclusion in the chain of events of new mechanisms. The disease pneumonia, the stages of its development are well studied. The occurrence of meningitis in pneumonia is a complication with a specific P., usually not occurring in pneumonia. But, once having arisen, meningitis establishes a series of new correlative connections having no relation to pneumonia. Arteriosclerosis of the brain has a certain picture of the disease, conditioned by the correlation of a number of mechanisms and processes. But, once having arisen on the basis of arteriosclerosis, a cerebral hemorrhage at the same time becomes a new starting point for possible complications, for example for the development of acute ulcers in the stomach, bedsores, cystitis, pyelonephritis with subsequent sepsis etc. Unusual reactions arising from the very beginning of the disease are the cause of the development of so-called atypical forms of disease. If we observe the development of typhoid fever without changes in the abdominal cavity (typhus sine typho), this is atypical and testifies to the falling out of a whole group of mechanisms which participate in the normal picture of typhoid fever. If typhus runs without a rash, when we speak of its atypicality, we thereby emphasize the falling out of the usual correlative connections leading to the eruption. It is however possible that the atypicality of diseases is based not only on the falling out of mechanisms already known to us, but also on the inclusion of special, unusual for this disease mechanisms. Sometimes special correlations arising from the very beginning of the disease lead to the creation of such disease forms which we are even inclined to designate as special nosological units, since these diseases do not fit into our concepts of the atypicality of something already known to us. The complexity, ramification of pathogenetic mechanisms, their correlations is the most important prerequisite for the exceptional diversity of disease forms observed by us. Moreover, this diversity is a completely regular phenomenon, since one of the most essential aspects of P. is the considerable variability of pathogenetic mechanisms, their continuous evolution during life in connection for example with age. A very important aspect in the problem of correlation is the question of antagonism and synergy of phenomena. By the first we mean such a relationship of two or more phenomena when the development of one of them excludes or slows down the development of another. The antagonism of pathological phenomena, and often of entire nosological categories, lies at the basis of that chapter of nosology which treats of the combination of diseases (see). This antagonism is already used in practical medicine (treating one disease with another).—The vast majority of processes observed in the organism in the course of this or that disease arise sequentially as a pathogenetic correlation of them, as synergy, but the latter can also be of another kind, when a number of processes arise simultaneously on a common pathogenetic basis. Only in this way can one imagine so-called systemic diseases, for example of the hematopoietic, reticulo-endothelial apparatus, lymph glands, serous cavities, connective tissue, some glands of internal secretion (see polyglandular syndromes) etc. The community of physiological functions dictates here the community of expression, to a certain degree the inevitability of such community. The most important mechanisms of development of pathological processes and diseases. 1. In toxicology and infectious pathology one can speak of direct damage to tissues in the process of absorption of this or that substance (for example of mercuric chloride, cholera endotoxin) by the surface of mucous membranes. One should however keep in mind the considerable difficulties which are inevitable in distinguishing such processes arising during the absorption of pathogenic substances from processes arising from direct damage to the absorbing surface by this or that substances, as well as from the excretion of corresponding substances by the same surfaces. As for the occurrence of pathological processes along the course of absorption, for example of a poison, such a mechanism in itself seems completely obvious. On the other hand, there is no doubt that the majority of poisons in the broad sense of the word are absorbed without special damage to the absorbing surface; moreover—the absorption itself to a certain degree presupposes the integrity of the absorbing apparatus throughout its entire extent. What we are often inclined to interpret as damage during absorption is in fact for the most part not such and is conditioned either by direct action, for example by coagulation of the proteins of the mucous membrane (and such coagulation rather hinders than promotes further absorption), or the visible damage arises from a completely opposite mechanism, namely—the excretion of the poisonous substance and usually not in the original, but in some way or other already changed, denatured form. Dust inhaled with air, depending, on the one hand, on its nature, on the other—on the sensitivity to this dust on the part of the pulmonary parenchyma, can pass through the alveolar barrier without any damage to it, but can cause desquamative and even pneumonic processes. These processes will express the direct action of the dust on the lung.

Dust absorbed by the lymphatic system of the lung produces a series of changes along this system (sclerosis, obliteration of vessels, etc.), which in turn becomes some obstacle to further absorption and transport of dust. In any case, the absorbed dust still moves in a centripetal direction, a significant part of it penetrates into the thoracic lymphatic duct, and, again entering the lung, is excreted here from the bloodstream, causing new changes along the absorbing, i.e., lymphatic, system of the lung. Sublimate, taken into the gastrointestinal tract, at the first moment produces an undeniable effect on the mucous membranes, simultaneously transforming into a new product—mercuric albuminate—which, without producing special changes along the absorbing system, is later excreted by various systems, especially by the kidneys, intestines, salivary and mucous glands of the oral cavity, etc. This excretion is accompanied by significant changes in the listed organs, and the best proof that these damages owe their origin precisely to excretion, and not to absorption or direct damage*, is that even in parenteral poisoning (e.g. per vaginam) these damages are topographically and fundamentally the same. P. of dysenteric, choleraic changes in the intestine, P. of uremic, septic colitis, etc. also illustrate the enormous importance of excretory processes as the pathogenetic basis of these changes. Thus, the pathogenetic significance of the act of absorption, on the one hand, is not subject to dispute even where no special changes occur in the absorbing organ itself during absorption. The very act of absorbing something at the same time leads to a change in the properties of what is being absorbed (physical, chemical, biological); in other words, the same substance during absorption and excretion is actually different; its pathogenetic significance will also be different. The complexity of the phenomena lies, however, not only in the fact that the substance being absorbed or excreted is always new in itself and that the relationship to it from the side of the organism is new, but also in that in the process of interaction with this substance, a series of new products arise from the side of the organism itself, subject to excretion or new absorption, and each new product may have its own pathogenetic properties. The basic error in the interpretation of the problem of infection in the bacteriological era was precisely the view that infection and the organism are only two warring sides. Both the infect and the organism in the process of their interaction continuously generate a huge number of new pathogenic factors, which may also have their own significance in the pathogenesis of the disease, e.g. products of metabolism; the excretion of these products or new absorption may have no less, and even greater, significance than the absorption and excretion of the infect itself. While acknowledging the enormous importance of excretory processes in P., we still do not have adequate information on how to understand this mechanism and how the excretion of corresponding substances produces this or that pathological effect. It can probably be stated that this effect is not always direct in the sense of immediate damage (degeneration, necrobiosis) to the excretory elements and systems. It is necessary to keep in mind the effect of pathogenic factors on the entire given excretory apparatus, including its nervous mechanisms and vascular system. However, it would be incorrect to view the excretory processes occurring under pathological conditions as necessarily pathogenic. Not only certain toxins but also entire microorganisms can pass through excretory systems without special changes in the latter, an example of which could be bacteriocholia, bacteriuria in typhoid fever; only in individual cases of the latter is inflammation of the kidneys or the biliary system observed in this connection. On the other hand, the question of the pathogenic significance of excretory processes does not reduce only to the fact of damage to the corresponding excretory organ; in the same typhoid fever, the moment of passage of typhoid bacilli through the liver and biliary paths apparently has important significance in the general chain of pathogenetic factors for the development of the general picture of typhoid; for in the experiment it is precisely by introducing bacilli into the gallbladder that one can best infect an animal. Thus, excretory processes, like resorptive ones, can only be a link in the general chain of pathogenic factors, sometimes remaining as such (locally) non-pathogenic. There is no doubt that under pathological conditions the function of excretory mechanisms can be possessed by those surfaces of the body (mucous membranes, serous membranes, skin) and those organs which under physiological conditions possess this function only to a slight degree. Excretion of nitrogenous wastes by the skin, mucous membrane of the pharynx, trachea, intestine, stomach, uterus, vagina, serous membranes (pleura, pericardium) is either entirely absent or negligible in normal conditions; in renal insufficiency such excretion can play a compensatory role of great significance. But this same function can also be pathogenetic, since in connection with such excretion severe necrobiotic and inflammatory processes are possible (uremic pharyngitis, laryngo-tracheitis, vaginitis, pericarditis, enterocolitis, etc.). In normal conditions the intestine only resorbs and changes bile pigments; in congenital absence of bile ducts discoloration of fecal masses is often observed, which can be explained only as a result of excretion of pigments by the intestine, as a new function of the latter under new (pathological) conditions. 2. The mechanisms related to the vascular system, with the dynamics of blood and lymph circulation, have enormous significance in the P. of diseases. While emphasizing this significance of the vascular system, it is at the same time necessary to warn against attributing decisive importance to the mere fact of transportation of something for the occurrence of a pathological process. The latter is above all a derivative of the place of transportation: dissemination of some pathological substrate throughout the body by the bloodstream is by no means equivalent to generalization of the process; it may not occur (see below). On the other hand, if we ascribed to the vascular system only the role of a transporting factor, we would commit no less a gross error, since both blood and lymph are media of the organism, by no means passively related to the objects being transported. These objects can in this medium undergo such essential changes that the very question of the possibility of generalization is either completely removed or the form of the latter is changed. Lymphogenic mechanisms are usually recognized by the processes that arise along the lymphatic system (lymphangitis, metastases in glands, etc.). On the other hand, the absence of these processes by no means removes the question of lymphogenic pathways of spread, since both infection and tumor cells can apparently pass certain segments of the lymphatic system without leaving special changes in them, and questions of local immunity have decisive significance here: primary cancer of the lung as a rule is combined with lymphangitis and regional lymphadenitis; tuberculous reinfection, however, hardly knows these processes, although it is difficult to imagine that absorption of the infect does not occur along these pathways. The greatest significance is attached to hematogenic mechanisms, since the circulation of pathogenic agents with the bloodstream most of all ensures both the rate of development of various processes and the volume of the latter. The simplest example of the use of a hematogenic mechanism is embolism. To hematogenic mechanisms also belong all processes of adsorption and phagocytosis (Speicherung of German authors) on the part of the 'coastal cells' of the circulatory system, in particular the so-called reticulo-endothelium. Processes of adsorption and absorption, i.e. the uptake and dissolution in the protoplasm of adsorbed substances, are accompanied by a change in the pH of the medium, an increase or decrease in the surface tension of its elements, a change in the contours and volume of the cell as well as a violation of cellular connections (desquamation, discomplexation); later to this are added moments of cellular proliferation, i.e. certain prerequisites are created for the development of hyperplastic, inflammatory and degenerative-necrobiotic foci. The nature of the colloids adsorbed by the coastal cells is apparently diverse; these include bacterial bodies, toxins, products of metabolism suspended in the blood, in particular products of decomposition of protoplasm, proteins, lipoids. It is undoubtedly true that moments of adsorption and phagocytosis are one of the most important prerequisites for the development of various pathological and in particular morphological processes, as well as phenomena of great clinical significance. These processes, as just indicated, are always connected with certain structural changes in the walls of blood vessels, and from the pathogenetic point of view all these changes undoubtedly indicate a change in vascular permeability, and consequently a violation of barrier functions (see) of the corresponding organs. The degree of such a barrier violation is directly proportional to the degree of changes in the cellular-coastal, i.e. vascular, apparatus of the given organ.

Violation of the blood-brain barrier is the main pathogenetic prerequisite for the development of encephalitis; with violation of the liver barrier, some forms of infectious jaundice can probably be connected. From the same point of view, it is possible to approach the question of albuminurias (violation of the renal barrier), alimentary intoxications, hemorrhagic diathesis, congenital infection, etc. 3. Intracanalicular (intratubular) mechanisms are of importance not so much for the origin as for the spread of already arisen processes (see below). These include, for example, those cases of pulmonary tuberculosis when virulent masses from some focus are aspirated along the bronchial tree system, affecting new parts of the lung parenchyma. From the same point of view, isolated tuberculous lesions of glandular organs are considered, such as: tuberculosis of the kidneys, sexual organs; such are forms of ascending nephritis, some forms of parotitis, pneumonias, cholangitis, etc. In all these cases, it is assumed that pathogenic agents descend or ascend along the glandular passages, excretory ducts; hence the corresponding terminology, e.g. ascending or descending pyelonephritis, etc. Intracanalicular mechanisms rarely have an independent character. Usually, with them, the action of additional mechanisms is not excluded, e.g. lymphogenous, hematogenous; the so-called ascent of infection (along the bile, sexual, urinary pathways) often combines or is preceded by disorders of secretion itself in the sense of change in the quality and quantity of secretion, its reaction, etc. 4. Close to the above are the mechanisms of spread of pathological processes in the order of direct continuation (per continuitatem) and by contact of two surfaces (per contiguitatem). In the first case, it is assumed that the expansion of the pathological process goes by the direct action of pathogenic factors on the nearest healthy areas. For example, tuberculosis of the spine, gradually involving the periosteum and surrounding cellular tissue, can later pass to the abdominal aorta and emerge into its lumen. Loose tissues in this case prove to be the most easily passable (subcutaneous tissue, soft meninges), while dense ones present considerable difficulties, which is also reflected in the rates of development of the entire condition. For example, in the conditions of pneumoconiosis, tuberculous processes in the lung proceed sluggishly and with marked chronicity; the same phenomenon is also observed in relation to lung cancers in pneumoconiotics: the rate of growth of tumors in these conditions can be slowed down several times. Spread per contiguitatem assumes contact of some pathological surface with a normal one and the subsequent disease of the latter; these include parietal peritonitis, pleurisy in areas of lesion of the visceral peritoneum or pleura, cases of implantation on the peritoneum of cells of a cancerous neoplasm; implantation on the upper lip of cancer of the lower lip, etc. It should however be pointed out that in all these cases of contact spread, we are dealing not with a simple inoculation of a pathological phenomenon onto a normal surface; such an inoculation is always preceded by one degree or another of damage to this surface, at least in the form of loss of its epithelial covering. On the other hand, of course, one must take into account, in addition to the indicated damage, the state of the substrate where implantation takes place. 5. Mechanical and physical factors, in particular muscular work, occupy a prominent place among pathogenic factors. Increased pressure of some parts of the body on others can cause, for example, atrophy of the latter, similar to how a pressure aneurysm of the aorta causes atrophy and erosion of the bone. This same pressure can cause displacement of organs, violation of their functions; for example, with strong intestinal distension, the high position of the diaphragm can disturb the function of respiration and blood circulation. On the contrary, a decrease in pressure, resp. counterpressure, can also be pathogenic, as can be seen in examples of obliteration of vessels for some reason excluded from the bloodstream, or in the example of the development of pulmonary atelectasis, when a certain area of the lung loses connection with the external environment due to obstruction of the leading bronchus by secretion. Certain muscular tensions have essential significance in the pathogenesis of various disorders, such as: cough, defecation, transition from sitting or lying position to standing, etc. Strong muscular tensions, increasing metabolism and blood pressure, affecting blood distribution, can cause acute decompensation and paralysis of the heart, for example in the presence of a defect of the latter. Muscular tension, even physiological, can cause, for example, detachment of mural thrombi (on the heart valves, somewhere in the venous system of the body) and lead to the development of embolic processes, often fatal. The connection between intense muscular work and hypertrophy of the musculature is well known; it is true that the entire mechanism of development of such working hypertrophy remains still unclear; it is undoubtedly that it includes the participation of the nervous apparatus, trophic factors, etc. Being a compensating factor, muscular hypertrophy, developing further, carries within itself the possibility of transformation into its opposite, into decompensation (degeneration, weakening of function, paralysis). Not only increased muscular tension can be pathogenic, but often the opposite state is pathogenic, namely- prolonged absence of movement, rest of the body, as evidenced by the recent past of surgical and obstetric practice, when prolonged lying of patients or parturients, lowering their blood pressure and metabolism, to a certain degree favored thrombus formation, as well as the development of hypostases, bedsores, etc. The physician's acquaintance with this pathogenic factor dictates to him the corresponding mode of action, such as: as early rising as possible, the necessity of at least passive movements, etc. The pathogenic significance of the statics of the human body follows from acquaintance with such processes as kyphoscoliosis, rickets, orthostatic albuminuria, flat foot, etc. The mechanical factor probably underlies the uneven thickening of arterial walls (their intima)-a circumstance having some significance for explaining, for example, the localization of atherosclerosis: atherosclerotic plaques and diffuse scleroses are often preferentially located in places of greatest friction of the blood column, as well as in areas where this column encounters particularly strong mechanical obstacles, for example immediately above the aortic valves. 6. Neuropsychic mechanisms. Under these are understood all sorts of influences coming from both the central and peripheral nervous systems and having as their point of application one or another area of the body, its system or the organism as a whole. The extreme complexity of psychic reactions themselves, as well as of neuro-functional mechanisms in the somatic area, their insufficient study under physiological conditions make natural the enormous difficulties in applying these mechanisms to the explanation of one or another pathological phenomenon. (On the significance of consciousness and the psyche in pathology and medicine-see the corresponding words.) However complex the neuropsychic mechanism of development of one or another suffering (mental, somatic) may be, the realization of the latter at the local level always goes with the most active participation of the autonomic nervous system. The latter has exceptionally important significance in questions of pathogenesis, and this is quite understandable due to the direct relation of this system to vasomotor activity, smooth muscle activity, secretion of glands, regulation of temperature, blood circulation, metabolism, etc. Autonomic-nerve mechanisms underlie a whole series of affections of the heart, blood vessels, digestive tract, respiratory tract, many nervous, endocrine diseases, etc. If modern pathology is unable to indicate with sufficient accuracy the details of neuropsychic mechanisms, then on the other hand, it will not be a great exaggeration to say that it is precisely the mechanisms affecting the character of blood circulation and the character of metabolism in organs or in the organism that are fundamental. Pathogenetic neurogenic mechanisms can be of central or local, reflex-arc origin. In the first case, we are talking about one or another pathological processes in the so-called vegetative centers (corpus striatum, intermediate, middle, medulla oblongata, spinal cord); in the second case, the source of pathogenic influences is the peripheral ganglionic apparatus. The most studied are the mechanisms having as their object of influence the circulatory system. Questions of redistribution of blood masses within the organism, the problem of collapse, the problem of blood filling, and to some extent also of the qualitative composition of the peripheral blood (e.g. content of leukocytes in it) are undoubtedly most closely connected with neurogenic mechanisms. The problems of hypertension, hypotension, angiospasm, apoplexy are from the pathogenetic side nervous problems and of primary importance. However, what has been said by no means exhausts the entire significance of neurogenic mechanisms.

The latter, especially in infectious diseases, play a significant role in the origin of diffuse catarrhs of mucous membranes; mucous membranes therefore easily become the site of introduction of one or another secondary infection. Neurogenic factors underlie the disruption of motor and secretory functions of various organs, causing for example decrease or increase in secretion from the salivary glands, stomach (achylia), intestine (constipation, diarrhea), not to mention disturbances of trophism (bedsores), paralyses, disturbances of conductivity and excitability of the heart muscle (transient blockades, extrasystole), etc. In general, it is difficult to imagine even the most elementary pathological process that would not be pathogenetically related in one way or another, initially or subsequently, with the nervous system (regional or central). In close connection with neurogenic mechanisms stand endocrine, ion-endocrine and chemical factors (for their significance and interrelationship see Internal Secretion, Metabolism). From all of the above it follows that pathogenetic mechanisms are extremely complex; however, it would be incorrect to think that these mechanisms exist separately and that in each specific case of disease one could always build a theory of its P. on the basis of one and only mechanism, e.g., hematogenous or neurogenic, etc. As a rule, we have an interaction of the indicated mechanisms, and in each specific case among the acting mechanisms leading and auxiliary ones can be distinguished. If we have before us a picture of generalized miliary tbc, we put forward as the basic pathogenetic factor the hematogenous factor of contamination of the organism with bacilli. We subordinate to this factor the disruption of barrier functions in a series of organs, in particular in the brain, explaining by this additional mechanism the occurrence in the same subject of tuberculous meningo-encephalitis. In the same order are subordinated the neurogenic mechanisms, automatically included by the very fact of severe damage to the central nervous system (Kernig's symptom, convulsions, vomiting, involuntary urination, etc.). In essential hypertension the leading pathogenetic principle is undoubtedly the neurogenic vegetative factor, but at the same time it does not remain the only one: the subsequently developing sclerosis of renal arterioles often causes insufficiency of the latter, retention of waste products, and along with that a new mechanism of new pathological phenomena called uremia, with the bright participation of hematogenous and excretory mechanisms. Pneumoconiosis has basically an aerogenous mechanism of origin, but the spread of dust through the lung is impossible without the participation of the lymphatic and intracanalicular (i.e., bronchial) system. This however is not all: the dust-laden lung and the mediastinal glands systematically deliver coal pigment into the bloodstream, and the latter, again but now hematogenously, is transported back to the lung. All these examples show how important it is in each specific case to determine not only the total sum of pathogenic mechanisms, but also the leading one. It is also very important to separately determine the role and interrelationship of the mechanism of origin and the mechanisms of spread in the development of pathological processes. The theoretical analysis of questions of the origin of pathological foci, especially in the field of infectious pathology, showed that the problem of origin actually covers two different questions: the mechanism of penetration of the pathogenic factor and the origin of the pathological focus as a result of this penetration. Indeed, penetration of the tuberculous virus into the organism can occur through the intestine, yet the origin of the primary focus can take place not in it, but e.g., in the lung. The penetration of tuberculous bacilli through the placenta in typical cases is established by the occurrence in the fetus of a primary focus in the liver and in its portal glands, but quite often this focus arises in the lung, simulating aerogenous penetration of infection. It has long been considered indisputable that the intestinal form of anthrax indicates enterogenicity both in the sense of penetration of infection and in the sense of origin of corresponding foci. Practice and experiment showed that this is by no means necessary, that damage to the intestine can easily occur in other forms of the disease, e.g., cutaneous, in the order of hematogenous localization. Questions of penetration, origin and spread acquire great practical significance when properly illuminated. The role of substrate in pathogenesis. The substrate (tissue, organ) where a given clinical-anatomical picture unfolds has enormous significance in P. suffering, and to a certain degree independently of whether the paths leading to this substrate will be lymphatic, blood vessels or some others. One can assert that the form, volume, tempo of the pathological process depend to a large extent on the function and structure, in particular angioarchitecture, of the organ (or tissue), its biochemical structure, the microflora of a given surface, and finally the degree of sensitivity to the etiological factor. For example, in dissemination of the tuberculous virus in children and adolescents, localization of the tuberculous process is especially often osseous (and specifically metaphyseal), urogenital. The localization of atherosclerosis in certain sections of the arterial bed is most closely connected with structural peculiarities of the vessels on their different extents, with the dynamics of lymphatic and blood circulation in these sections, with peculiarities of metabolism, in particular of lipoids, in the vessel wall. For the formation of metastases of cancer in one or another organ, the mechanical factor of carriage and entrapment of tumor particles is by no means sufficient. Only in those cases when the given substrate, by its physico-chemical and biochemical properties, is suitable for the development of cells of a given tumor, is metastasis of the latter possible. Only in this way can one imagine the so-called selective metastasis of one or another cancer to certain organs (see Tumors). Toxins and poisons of one or another origin, entering the general bloodstream and organs, in particular the kidney, cause in different parts of these organs by no means the same changes; for example, necrosis of the epithelium of the convoluted tubules can be observed with the complete preservation of the epithelium of the straight tubules. The pronounced tendency to damage the putamen of the brain in poisoning with carbon monoxide cannot be interpreted otherwise than as a special affinity of these ganglia for CO. In the same plane apparently should be resolved questions concerning generally symmetrical lesions in the organism, although here it is necessary to take into account also the symmetry of the organism in neurological and angioarchitectonic relations. In any case, what in pathology bears the designation of 'selectivity' of lesion, or what is designated as 'locus minoris resistentiae', or what is included under the concept of 'affinity', 'patoclinicity,' etc.,—all this in the final analysis is an emphasis on the special role and significance in P. of the substrate itself, its anatomophysiological and biochemical individuality. It is necessary to emphasize that the very concept of substrate from a pathogenetic point of view by no means necessarily implies units in the form of organs; on the contrary, the doctrine of P. readily dissects organs into constituent elements, this or other tissues, and often takes precisely these latter as the basic basis in the unfolding of the pathological picture. We are accustomed for example to say that rheumatism affects the heart, that it often affects fasciae, aponeuroses, tendon sheaths, tonsils, etc., whereas in reality here we are speaking not so much about the lesion of the heart or tonsils as organs, as about the selective lesion of precisely fibrous tissue in these organs, in particular the heart valves, since they are built from the same fibrous tissue as aponeuroses, fasciae and capsules. That is why the interpretation of rheumatism as 'fibrositis' undoubtedly corresponds to reality. If we say that atherosclerosis is not only a disease of arteries, then here too the intention is to emphasize not so much the vulnerability of arteries as organs (clinically this remains most important) as the lesion of that connective tissue, those para-plastic substances that participate in the construction of these organs. And indeed, the fact of lesion of the interstitial tissue of the kidneys, muscle tendons by atherosclerosis speaks in favor of such a position. Thus, pathogenetically the substrate is by no means confined within the boundaries of known organs: the pathological substrate under certain conditions can be any tissue (e.g., connective tissue) as a certain anatomophysiological system; for it is on precisely these bases that we speak of the reticuloendothelial system, which does not have a unified organic base. The microflora of a given place has enormous significance in the realization of local processes. If in uremic excretory pharyngitis, tracheitis, enterocolitis we observe the development of gangrenous-diphtheritic lesions, or if in obstruction of the mesenteric arteries we observe not simply necrosis, but gangrene of the intestine, then these phenomena are explained precisely by the participating role of the microflora of the intestine, pharynx, trachea. In the same plane finds its explanation the pathogenesis of traumatic pneumonia with diplococci in the exudate.

The microflora of organs (physiological) has enormous significance in pathology as an additional or 'para-infectious' factor; this also includes everything related to the so-called secondary infections. The degree and character of the substrate's sensitivity are of no less pathogenetic importance. The introduction of horse serum into a normal rabbit gives a negligible inflammatory reaction, clinically equal to zero; the introduction of the same serum into a sensitized (by the same serum) rabbit gives a hyperergic, i.e., necrotizing, inflammation, which immediately strikes the eye clinically and anatomically as an unusual phenomenon (Arthus phenomenon). The significance of the substrate's reactivity in the entire doctrine of Pathogenesis is being increasingly emphasized today. Manifestations of increased sensitivity are seen, for example, in lobar pneumonia, the lobar volume and rapid rate of development of which do not fit into simple mechanical schemes of Pathogenesis. The same view should be taken of endocarditis, which develops only under conditions of special sensitivity of the endocardium to the corresponding infection. The former doctrine of thrombosis cannot be considered satisfactory, where particular emphasis was placed on the role of purely mechanical factors in Pathogenesis (damage to the wall, slowing of the current, etc.); the active role of the vascular wall itself, the degree of its sensitivity, etc., was overlooked. --From the entire formulation of the pathogenetic problem, it follows that this problem is exceptionally broad. (Pathogenesis of individual diseases and processes--see the respective terms.)