Glucocorticoid physiology, pharmacology and stress.
Glucocorticoid physiology, pharmacology and stress.
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DOI：
10.1007/978-1-4684-5101-6_6
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发表时间：
1986
影响因子：
--
通讯作者：
A. Munck;P. Guyre
中科院分区：
文献类型：
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作者：
A. Munck;P. Guyre
众所周知，通过对碳水化合物代谢的影响和对其他激素作用的“允许”作用，通过负反馈调节维持糖皮质激素的基础水平来调节广泛的生理过程。糖皮质激素水平在任何威胁体内平衡的应激反应中急剧增加。传统上认为，这种增加的水平是为了增强生物体对压力的抵抗力。然而，已知的高水平糖皮质激素的生理和药理作用是如何实现这一功能的，一直是个谜。开始出现的一种概括是，许多这些影响可能是继发于糖皮质激素对许多细胞间介质（包括既定激素、前列腺素、中性蛋白酶和干扰素等细胞因子）作用的调节。这些介质参与生理机制-内分泌，肾脏，免疫，神经等-建立第一道防线，抵御出血，代谢紊乱，感染，焦虑等对体内平衡的挑战。与糖皮质激素在应激中的作用是增强这些防御机制的传统观点相反，越来越清楚的是，中度至高水平的糖皮质激素通常会抑制这些防御机制。当糖皮质激素被发现是抗炎剂时，这种矛盾首次出现，并且一直是糖皮质激素功能统一图景的主要障碍。我们已经提出，压力引起的糖皮质激素水平的增加并不是防止压力本身的来源，而是防止身体对压力的正常反应，防止这些反应过度并威胁到体内平衡。这一假说的种子可以在许多早期关于糖皮质激素作用的讨论中找到，它立即解释了上述悖论，并为糖皮质激素生理学提供了一个统一的概念框架，可以适应诸如碳水化合物代谢、炎症过程、休克和水平衡等明显不相关的生理和药理作用。这也导致我们提出一些酶被糖皮质激素迅速诱导解毒介质释放在应激诱导的初级防御机制激活；如果不加以控制，这些调解人本身可能造成损害。
Basal levels of glucocorticoids maintained by negative feedback regulation are known to modulate a wide range of physiological processes, through a variety of effects such as those on carbohydrate metabolism and “permissive” actions on effects of other hormones. Glucocorticoid levels increase sharply in response to the stress of any kind of threat to homeostasis. The increased levels have traditionally been ascribed the function of enhancing the organism’s resistance to stress. How known physiological and pharmacological effects of high levels of glucocorticoids might accomplish this function, however, has been a mystery.A generalization that is beginning to emerge is that many of these effects may be secondary to modulation by glucocorticoids of the actions of numerous intercellular mediators, including established hormones, prostanoids, neutral proteinases, and cytokines such as interferon. These mediators participate in physiological mechanisms — endocrine, renal, immune, neural, etc. — that mount a first line of defense against such challenges to homeostasis as hemorrhage, metabolic disturbances, infection, anxiety, and others.Contrary to the traditional view that the role of glucocorticoids in stress is to enhance these defense mechanisms, it has become increasingly clear that glucocorticoids at moderate to high levels generally suppress them. This paradox first emerged when glucocorticoids were discovered to be antiinflammatory agents, and had remained a major obstacle to a unified picture of glucocorticoid function.We have suggested that stress-induced increases in glucocorticoid levels protect not against the source of stress itself but rather against the body’s normal reactions to stress, preventing those reactions from overshooting and themselves threatening homeostasis. This hypothesis, the seeds of which are to be found in many earlier discussions of glucocorticoid effects, immediately accounts for the paradox noted above, and provides glucocorticoid physiology with a unified conceptual framework that can accommodate such apparently unrelated physiological and pharmacological effects as those on carbohydrate metabolism, inflammatory processes, shock and water balance. It also leads us to propose that some enzymes rapidly induced by glucocorticoids detoxify mediators released during stress-induced activation of primary defense mechanisms; those mediators could themselves cause damage if left unchecked.