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1、 n engl j med 353;16www.nejm.orgoctober 20, 2005Thenew england journal ofmedicine1711review articlemechanisms of diseaseAntiinflammatory Action of Glucocorticoids New Mechanisms for Old DrugsTurk Rhen, Ph.D., and John A. Cidlowski, Ph.D.From the Department of Biology, Univer- sity of North Dakota, G
2、rand Forks (T.R.); the Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, Research Triangle Park, N.C. (J.A.C.); and the Department of Health and Human Services, National Institutes of Health, Bethesda, Md. (J.A.C.). Address re- print requests to Dr. Cidlowski at
3、 the Lab- oratory of Signal Transduction, National Institute of Environmental Health Sciences, 111 T.W. Alexander Dr., Research Triangle Park, NC 27709, or at cidlows1niehs. nih.gov.N Engl J Med 2005;353:1711-23.Copyright 2005 Massachusetts Medical Society.nflammation is a reflexive response to infe
4、ction, thebindingof antibodies to antigens within the body, mechanical irritation, or injury.1Mi- crobes that breach epithelial barriers, for instance, directly activate complement and toll-like receptors, two principal components of the innate immune system. The activation of these sentinels trigge
5、rs the synthesis and release of inflammatory media- tors with acute effects on the vasculature. Localized vasodilation, increased vascular permeability, extravasation of plasma (and humoral) proteins, and migration of leuko- cytes into the affected tissue produce the classic signs of inflammation: c
6、alor, dolor, rubor, tumor, and functio laesa. A positive feedback loop initiates the production of ad- ditional inflammatory cytokines once infiltrating leukocytes become activated. Antiin- flammatory homeostatic mechanisms reverse these processes as the infectious agent is cleared by the innate and
7、 adaptive immune systems. The hypothalamicpituitary adrenal axis and glucocorticoids in particular are essential in limiting and resolving the inflammatory process.2Whereas restricted inflammation is beneficial, excessive or persistent inflammation incites tissue destruction and disease. Together, i
8、nflammatory disorders such as aller- gies, asthma, autoimmune diseases, and sepsis are a major cause of illness and death. Asthma affects approximately 21.9 million adults and 8.9 million children in the Unit- ed States alone. The prevalence of autoimmune diseases, which affect 8.5 million Americans
9、,3,4is also noteworthy. Rheumatoid arthritis, Graves disease, glomerulone- phritis, type 1 diabetes mellitus, multiple sclerosis, thyroiditis, pernicious anemia, sys- temic lupus erythematosus, psoriasis, and vitiligo account for most of these autoim- mune diseases. Sepsis is fatal for roughly 30 pe
10、rcent of the 700,000 patients affected annually in the United States.5-7Glucocorticoids are indicated for the treatment of many of these diverse conditions. The efficacy of glucocorticoids in alleviating inflam- matory disorders results from the pleiotropic effects of the glucocorticoid receptor on
11、multiple signaling pathways. Pleiotropy can, however, also have adverse effects: growth retardation in children, immunosuppression, hypertension, inhibition of wound re- pair, osteoporosis, and metabolic disturbances. All these harmful properties contrain- dicate prolonged glucocorticoid therapy. He
12、re, we review mechanisms whereby gluco- corticoids inhibit inflammation and the therapeutic limitations of these hormones. We then provide a prospectus for research on drugs that dissociate the beneficial and det- rimental effects of glucocorticoids. The hypothalamicpituitaryadrenal axis plays a cen
13、tral role in regulating signaling by the glucocorticoid receptor, which is expressed in virtually all cells. In brief, neural, en- docrine, and cytokine signals converge at the level of the periventricular nucleus of theibasic actions of endogenous glucocorticoidsCopyright 2005 Massachusetts Medical
14、 Society. All rights reserved. Downloaded from www.nejm.org on October 20, 2005 . This article is being provided free of charge for use in China. n engl j med 353;16www.nejm.orgoctober 20, 2005Thenew england journal ofmedicine1712hypothalamus to control the secretion of cortico- tropin-releasing hor
15、mone into the hypophyseal por- tal system (Fig. 1).2,8In turn, corticotropin-releas- ing hormone stimulates the release of corticotropin from the anterior pituitary. Corticotropin induces the synthesis and secretion of cortisol by the adre- nal cortex. Most of the secreted cortisol (approxi- mately
16、90 percent) is bound to corticosteroid-bind- ing globulins in the blood.9Free cortisol is the biologically active form of the hormone and is con- verted to cortisone by type 2 11b-hydroxysteroid dehydrogenase.10Conversely, type 1 11b-hydroxy- steroid dehydrogenase converts cortisone into cortisol.10The glucocorticoid receptor is a member of the steroid-hormonereceptor family of proteins.11,12It binds with high affinity to cortisol; the bound cor- tisol promotes the dissociation of
