期刊
AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY
卷 296, 期 5, 页码 R1376-R1384出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpregu.90962.2008
关键词
CD14; cyclooxygenase-2; NAPDH oxidase; inducible nitric oxide synthase; proinflammatory cytokines
类别
资金
- Division of Intramural Research Programs
- National Institute of Mental Health
Sanchez-Lemus E, Benicky J, Pavel J, Larrayoz IM, Zhou J, Baliova M, Nishioku T, Saavedra JM. Angiotensin II AT1 blockade reduces the lipopolysaccharide- induced innate immune response in rat spleen. Am J Physiol Regul Integr Comp Physiol 296: R1376-R1384, 2009. First published February 18, 2009; doi: 10.1152/ajpregu.90962.2008.- ANG II AT1 receptor blockade reduces inflammation in hypertension. To determine whether ANG II AT1 receptor blockers (ARBs) influence the innate immune inflammatory response in normotensive rats, we studied rat plasma and spleen after a 3-day subcutaneous pretreatment with the ARB candesartan followed by a single dose of the bacterial endotoxin LPS ( 50 mu g/kg ip). Peripheral administration of LPS to rodents produced a generalized inflammatory response with increased release of TNF-alpha, IL-1 beta, and IL-6 into the circulation. Candesartan pretreatment reduced the LPS-induced release of TNF-alpha, IL-1 beta, and IL-6 into the circulation. The red pulp of rat spleen expressed large numbers of AT1 receptors and the LPS receptors Toll-like receptor 4 and CD14. Candesartan administration significantly blocked AT1 receptors. The ARB reduced the LPS-induced upregulation of CD14 gene expression; expression of TNF-alpha and IL-6 mRNA and protein; expression of IL-1 beta and I kappa B-alpha mRNA; COX-2 mRNA and protein expression and PGE2 concentration; inducible nitric oxide synthase (iNOS) gene and protein expression and iNOS activity; and Nox2 gene expression and 8-isoprostane levels. In addition, candesartan reduced the CD14 protein expression in saline- and LPS-treated rats. Our results suggest that AT1 receptors are essential for the development of the full innate immune response to bacterial endotoxin. The ARB decreased the general peripheral inflammatory reaction to LPS and partially decreased the inflammatory response in the spleen. An unrestricted innate immune response to the bacterial endotoxin may have deleterious effects for the organism and may lead to development of chronic inflammatory disease. We postulate that ARBs may have therapeutic effects on inflammatory conditions.
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