General Adaptation Syndrome (GAS): Hans Selye is credited with creating the first definition of stress as a non-specific response of the body to any demand made upon it. Selye's theory about the effects of stress he demonstrated to be applicable to any sort of stress.
The 3 stages of the GAS are:
- Alarm Reaction: Similar to fight or flight.
- Resistance: Struggle to overcome, hard work, limited rest/sleep.
- Exhaustion: Body systems crash, fatigue, errors, irritability, vulnerable to illness (colds, flu, acne).
Non-specific stress response: Selye's theory was that injury, overload and fear all produce the same body reaction. He believed that both eustress and distress both produced the same response in the body. Both situations, he said, resulted in some degree of wear and tear in the body which finally accumulated to produce aging. This theory was over-simplified as you will see below.
A review was published by Selye in 1946, where he already gives a comprehensive theory of the general adaptation syndrome which is supported by experimental facts. He also talks about the possibility that diseases of adaptation do exist. He states that, after exposure to stress, initially there is shock, which is followed by a counter shock phase, and this gradually goes into a stage of resistance. If, however, the stressor persists, resistance may go into exhaustion and death may ensue. He points out that specific and nonspecific resistance follow the same course but this latter "cross resistance" will fall much sooner and stays below normal during the period of resistance. He also presents data of blood sugar and chlorine changes and points out that white blood cell counts rise invariably during stress, regardless of the stressor used. The changes in the adrenal cortex and of thymus involution are also illustrated histologically. The adrenal cortex becomes wider with loss of lipid granules and the border between the zona fasciculata and reticularis is no longer distinct. The thymus shows a depletion of cortical thymocytes. Nuclear debris is evident and pyknotic thymocyte nuclei are abundant. He notes that this "accidental involution" becomes most pronounced during the countershock phase when the adrenal cortex reaches its maximum development. Large macrophages engulf the dead thymus cells and carry them away through the lymphatics. At the same time he noted that thymic reticulum reverts to its origianl epithelial type and the cells become roundish or polygonal and rich in cytoplasm. When involution is most acute the entire organ is distended with jelly-like edema. He points out that lymph nodes, the spleen and other lymphatic organs are almost as markedly affected as the thymus, although they do not involute quite as rapidly and their involution cannot be completely prevented by adrenalectomy.
Today we know that a variety of insults, including trauma and infection stimulate the release of chemotactic-, proinflammatory cytokines, and a whole host of other mediators from a variety of cells in the damaged area that include mast cells, endothelial cells, platelets. The released mediators attract blood borne leucocytes, such as neutrophilic granulocytes, monocytes/macrophages, lymphocytes, eosinophils and basophils that release additional mediators, and thus contribute to the inflammatory response. In some cases certain cytokines, such as interleukin-1 (IL-1), tumor necrosis factor-a (TNF-alpha) and interleukin-6 (IL-6), become detectable in the blood and function as acute phase hormones. They act on the brain causing fever and other functional modifications (IL-1, TNFalpha), release certain pituitary hormones and inhibit others (much of which is indicated in the graph reproduced from his article), promote general catabolism, (mediated primarily by TNF-alpha, also known as cachectin), stimulate the production of new serum proteins known as acute phase reactants in the liver (the joint action of IL-6, glucocorticoids and catecholamines), and also elevate the production of leucoytes in the bone marrow, the mechanism of which is not fully elucidated. (For further reference, please see also the papers by Asa and Kovacs, Besedovsky and del Rey, Gaillard, and Nagy and Berczi in this volume.) Thus, with the recent discovery of cytokines and our increasing recognition of their functions, we have begun to fill in the gaps in Dr. Selye's adaptation syndrome outlined nearly half a century ago.
In 1949 Selye discovered that an inflammatory reaction, which can be induced in the rat by the parenteral administration of egg white, is inhibited by cortisone or by purified ACTH. On the other hand, desoxycorticosterone acetate, a mineralcorticoid compound, tends to aggravate the reaction. These experiments initiated his interest in inflammation which became the most lasting topic in his research and led to the proposition later that diseases, like rheumatoid arthritis, anaphylaxis, etc. are in fact diseases of adaptation as stated in numerous publications.
" Among the derailments of the general adaptation syndrome that may cause disease, the following are particularly important:
(i) an absolute excess or deficiency in the amount of adaptive hormones (for example, corticoids, ACTH, and STH) produced during stress; (ii) an absolute excess or deficiency in the amount of adaptive hormones retained (or `fixed') by their peripheral target organs during stress; (iii) a disproportion in the relative secretion (or fixation) during stress of various antagonistic adaptive hormones (for example, ACTH and antiphlogistic corticoids, on the one hand, and STH and prophlogistic corticoids, on the other hand); (iv) the production by stress of metabolic derangements, which abnormally alter the target organ's response to adaptive hormones (through the phenomenon of `conditioning'); and (v) finally, we must not forget that, although the hypophysis-adrenal mechanism plays a prominent role in the general-adaptation syndrome, other organs that participate in the latter (for example: nervous system, liver, and kidney) may also respond abnormally and become the cause of disease during adaptation to stress...
Corticoid requirements during stress: During stress, the corticoid requirements of all mammals are far above normal. After destruction of the adrenals by disease (as after their surgical removal), the daily dose of corticoids, necessary for the maintenance of well-being at rest, is comparatively small, but it rises sharply during stress (for example: cold, intercurrent infections, and hemorrhage), both in experimental animals and in man...
Anti-inflammatory effects of corticoids: The same antiphlogistic corticoids (cortisone and cortisol) that were shown to inhibit various types of experimental inflammations in laboratory animals exert similar effects in a human being afflicted by inflammatory diseaes (for example, rheumatoid arthritis, rheumatic fever, and allergic inflammations)...
"Sensitivity to infection after treatment with antiphlogistic corticoids. In experimental animals, the suppression of inflammation by antiphlogistic hormones is frequently accompanied by an increased sensitivity to infection, presumably because the encapsulation of microbial foci is less effective and perhaps partly also because serologic defense is diminished...
Psychological and psychiatric effects of corticoid overdosage: It has long been noted that various steroids - including desoxycorticosterone, cortisone, progesterone, and many others - can produce in a variety of animal species (even in primates such as the rhesus monkey) a state of great excitation followed by deep anesthesia. It has more recently been shown that such steroid anesthesia can also be produced in man, and, of course, the marked emotional changes (sometimes bordering on psychosis) that may occur in predisposed individuals during treatment with ACTH, cortisone, and cortisol are well known. Several laboratories reported furthermore that the electroshock threshold of experimentl animals and their sensitivity to anesthetics can be affected by corticoids."
The prediction by Selye that the pituitary gland has the capacity to both stimulate and inhibit inflammatory reactions is the subject of recent investigations and is proven correct. The notion of prophlogistic steroids has not been studied to a great extent to date, but the antiinflammatory effect of glucocorticoids is firmly established and it is clear today that the adrenal gland plays an important physiological role in the regulation of immune and inflammatory responses. The disproportion of hormones and other mediators, altered responsiveness in tissues and the significance of metabolic derangements during acute phase reactions related to sepsis, severe trauma and shock are the subject of current investigations and deemed to be highly relevant to prognosis. The involvement of the central nervous system, the liver and of other organs, such as the kidney, is also substantiated. That "conditioning" may also play a role in host defence is also gaining ground. Some hard evidence is forthcoming regarding the corticoid requirements during infection and other forms of stress. The antiinflammatory effect of cortisone and cortisol are well recognized and are widely applied in medicine today. That corticosteroids increase the sensitivity to infection is of common knowledge. The phenomenon of stress related anesthesia is well recognized, but opioid peptides rather than steroid hormones are considered to be the mediators.