Munck A, Guyre P M
Adv Exp Med Biol. 1986;196:81-96. doi: 10.1007/978-1-4684-5101-6_6.
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.
已知通过负反馈调节维持的糖皮质激素基础水平可通过多种效应来调节广泛的生理过程，比如对碳水化合物代谢的影响以及对其他激素效应的“允许”作用。面对任何一种对体内平衡构成威胁的应激源，糖皮质激素水平都会急剧升高。传统上认为，升高的糖皮质激素水平具有增强机体应激抵抗力的功能。然而，高水平糖皮质激素的已知生理和药理作用是如何实现这一功能的，一直是个谜。一个逐渐浮现的普遍观点是，这些作用中的许多可能是糖皮质激素对众多细胞间介质（包括已确定的激素、前列腺素、中性蛋白酶以及如干扰素等细胞因子）的作用进行调节的继发效应。这些介质参与了生理机制——内分泌、肾脏、免疫、神经等——这些机制构成了针对诸如出血、代谢紊乱、感染、焦虑等对体内平衡的挑战的第一道防线。与传统观点认为糖皮质激素在应激中的作用是增强这些防御机制相反，越来越明显的是，中到高水平的糖皮质激素通常会抑制它们。当发现糖皮质激素是抗炎剂时，这个悖论首次出现，并且一直是糖皮质激素功能统一图景的主要障碍。我们提出，应激诱导的糖皮质激素水平升高保护的不是应激源本身，而是机体对应激的正常反应，防止这些反应过度并自身威胁体内平衡。这个假说在许多早期关于糖皮质激素作用的讨论中已有端倪，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，该框架能够容纳诸如对碳水化合物代谢、炎症过程、休克和水平衡等明显不相关的生理和药理作用。它还促使我们提出，一些由糖皮质激素快速诱导的酶可使应激诱导的初级防御机制激活过程中释放出来的介质解毒；如果这些介质不受控制，它们本身可能会造成损害。
