The Thrombohemorrhagic Phenomenon as a Pluricausal Disease

THE THROMBOHEMORRHAGIC PHENOMENON AS A PLURICAUSAL DISEASE HANS SELYE* I. Introduction The concept that every well-characterizable specific disease entity is due to its own particular causative agent has gained acceptance mainly during the nineteenth century. The emergence ofmodern bacteriology under the influence of Semmelweis, Pasteur, Koch, and their contemporaries furnished countless examples in support ofthis view as applied to the microbial diseases. It became evident that the characteristic syndrome of any one infectious malady—such as tuberculosis, cholera, typhoid, or diphtheria —could be elicited only by its own specific kind of germ. Soon thereafter research in the fields of nutrition and endocrinology showed that the same principle is applicable there also. Such previously mysterious diseases as scurvy, pellagra, or rickets were each traced to the lack of one specific vitamin, while the most diverse endocrine derangements were found to result from the lack or excess ofparticular hormones, each compound being responsible for one kind of derangement only. These data were readily acceptable since they agreed with earlier observations in toxicology: it had long been known that poisoning with lead, arsenic, or certain plant extracts induces specific syndromes, each characteristic ofthe particular poison used. In the face ofall this well-documented evidence, it seemed that we must henceforth abandon the vague notions of our predecessors who thought that diverse diseases can result from a single cause and, conversely, that one and the same malady can be produced by different causative agents. * Institut de Médecine et de Chirurgie expérimentales, Université de Montréal, Montréal, Canada. This work was supported by the U.S. Army Medical Research and Development Command (Contract No. DA-40-103-MD-2039), the National Cancer Institute of Canada, and the Medical Research Council ofCanada. A monograph under this title is being published by Charles C. Thomas. 22Ó Hans Selye · The Thrombohemorrhagic Phenomenon Perspectives in Biology and Medicine · Winter 1966 The very idea that any one disease, say tuberculosis, might be due, in different patients, to malnutrition, heredity, excessive physical work, or emotional shock appeared to be as unscientific as the superstitions ofantiquity which attributed the most diverse maladies to the "evil eye" or thejealousy ofthe gods. Yet, there remained the disturbing fact that certain individuals are uncommonly resistant or susceptible to certain diseases; indeed, these "individual variations in disease proneness" can often be traced to, or even purposely modified by, identifiable factors. The concept ofthe "pluricausal diseases" attempts to analyze this "soil factor" by objective and, wherever possible, quantitative experimental techniques. Up to now one ofits most striking contributions was to show, on many disease models, that a variety of "sensitizing factors" can so prepare the organism that it will respond to certain "challengers" with a stereotyped reaction whose character can be predicted. In each case the quality of the expectable morbid lesion (e.g., inflammation, necrosis, calcification, thrombohemorrhagic changes) is determined by the sensitizer , but the disease proneness remains latent until a challenger is applied which makes a response manifest and determines its location. II. History It is in the course of our studies on the mechanism of stress-induced morbid lesions that we first became aware ofpluricausal diseases. We noted, for example, that the same non-specific stressor agent (e.g., exposure to cold) could either produce no disease or elicit quite selective lesions in certain organs (e.g., thymus, gastrointestinal tract, kidney) depending upon "conditioning factors." Apparently these modifying agents (e.g., diet, hormones, prior exposure to stress) can preferentially affect the sensitivity of certain organs and thereby determine the localization of disease [i, 2]. Inflammation is perhaps the most typical tissue response to non-specific topical stressors, and its regulation by pro- and antiphlogistic "stress hormones" is another example ofhumoral conditioning. Here a relative excess of prophlogistic agents can act as the "sensitizer," but it takes an appropriate tissue irritant to unmask the latent disease proneness thus induced and to determine thelocation ofthe resulting inflammatory response [2, 3]· Later it became possible to sensitize experimental animals for the pro227 duction ofa syndrome ofhyalinosis which furnished us with several models ofcollagen diseases, such as periarteritis nodosa and hypertensive nephrosclerosis . This sensitization was achieved by treatment with mineralocorticoids and dietary supplements of...