Angiotensin II AT1 blockade reduces the lipopolysaccharide-induced innate immune response in rat spleen
Angiotensin II AT1 blockade reduces the lipopolysaccharide-induced innate immune response in rat spleen
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DOI：
10.1152/ajpregu.90962.2008
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发表时间：
2009-05-01
影响因子：
2.8
通讯作者：
Saavedra, Juan M.
中科院分区：
文献类型：
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作者：
Sanchez-Lemus, Enrique;Benicky, Julius;Saavedra, Juan M.
Sanchez-Lemus E，Benicky J，Pavel J，Larrayoz IM，Zhou J，Baliova M，Nishioku T，Saavedra JM.血管紧张素Ⅱ AT 1阻断剂降低脂多糖诱导的大鼠脾脏先天性免疫反应。Am J Physiol Regul Integr Comp Physiol 296：R1376-R1384，2009。首次发表于2009年2月18日; doi：10.1152/ajpregu.90962.2008。ANG II AT 1受体阻断剂可减轻高血压的炎症反应。为了确定ANG II AT 1受体阻滞剂（ARB）是否影响血压正常大鼠的先天免疫炎症反应，我们研究了皮下预处理3天后，用ARB坎地沙坦，然后单剂量的细菌内毒素LPS（50 μ g/kg ip）的大鼠血浆和脾脏。对啮齿类动物外周给予LPS产生全身性炎症反应，增加了TNF-α、IL-1 β和IL-6向循环中的释放。坎地沙坦预处理可减少LPS诱导的TNF-α、IL-1 β和IL-6向循环中的释放。大鼠脾脏红髓表达大量的AT 1受体和LPS受体Toll样受体4和CD 14。坎地沙坦给药显著阻断AT 1受体。ARB降低了LPS诱导的CD 14基因表达上调; TNF-α和IL-6 mRNA和蛋白表达; IL-1 β和I κ B-α mRNA表达;考克斯-2 mRNA和蛋白表达以及PGE 2浓度;诱导型一氧化氮合酶（iNOS）基因和蛋白表达以及iNOS活性;以及Nox 2基因表达和8-异前列烷水平。此外，坎地沙坦降低了生理盐水和LPS处理大鼠的CD 14蛋白表达。我们的研究结果表明，AT 1受体是必不可少的发展的完整的先天性免疫反应的细菌内毒素。ARB降低了对LPS的一般外周炎症反应，并部分降低了脾脏中的炎症反应。对细菌内毒素的不受限制的先天免疫应答可能对生物体具有有害作用，并可能导致慢性炎性疾病的发展。我们推测ARB可能对炎症性疾病有治疗作用。
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.