Sanchez-Lemus Enrique, Murakami Yuki, Larrayoz-Roldan Ignacio M, Moughamian Armen J, Pavel Jaroslav, Nishioku Tsuyoshi, Saavedra Juan M
Section on Pharmacology, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, 10 Center Drive, MSC 1514, Building, 10, Room 2D57, Bethesda, Maryland 20892, USA.
Endocrinology. 2008 Oct;149(10):5177-88. doi: 10.1210/en.2008-0242. Epub 2008 Jun 12.
Peripheral administration of bacterial endotoxin [lipopolysaccharide (LPS)] to rodents produces an innate immune response and hypothalamic-pituitary-adrenal axis stimulation. Renin-angiotensin-aldosterone system inhibition by angiotensin II AT1 receptor blockade has antiinflammatory effects in the vasculature. We studied whether angiotensin II receptor blockers (ARBs) prevent the LPS response. We focused on the adrenal gland, one organ responsive to LPS and expressing a local renin-angiotensin-aldosterone system. LPS (50 microg/kg, ip) produced a generalized inflammatory response with increased release of TNF-alpha and IL-6 to the circulation, enhanced adrenal aldosterone synthesis and release, and enhanced adrenal cyclooxygenase-2, IL-6, and TNF-alpha gene expression. ACTH and corticosterone release were also increased by LPS. Pretreatment with the ARB candesartan (1 mg/kg.d, sc for 3 d before the LPS administration) decreased LPS-induced cytokine release to the circulation, adrenal aldosterone synthesis and release, and cyclooxygenase-2 and IL-6 gene expression. Candesartan did not prevent the LPS-induced ACTH and corticosterone release. Our results suggest that AT1 receptors are essential for the development of the full innate immune and stress responses to bacterial endotoxin. The ARB decreased the general peripheral inflammatory response to LPS, partially decreased the inflammatory response in the adrenal gland, prevented the release of the pro-inflammatory hormone aldosterone, and protected the antiinflammatory effects of glucocorticoid release. 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 the ARBs may have therapeutic effects on inflammatory conditions.
对啮齿动物外周给予细菌内毒素[脂多糖（LPS）]会引发先天性免疫反应并刺激下丘脑-垂体-肾上腺轴。通过血管紧张素II 1型受体阻断抑制肾素-血管紧张素-醛固酮系统在脉管系统中具有抗炎作用。我们研究了血管紧张素II受体阻滞剂（ARB）是否能预防LPS反应。我们重点关注肾上腺，这是一个对LPS有反应且表达局部肾素-血管紧张素-醛固酮系统的器官。LPS（50微克/千克，腹腔注射）产生全身性炎症反应，循环中肿瘤坏死因子-α（TNF-α）和白细胞介素-6（IL-6）的释放增加，肾上腺醛固酮合成和释放增强，肾上腺环氧化酶-2、IL-6和TNF-α基因表达增强。LPS还增加了促肾上腺皮质激素（ACTH）和皮质酮的释放。用ARB坎地沙坦预处理（1毫克/千克·天，在给予LPS前皮下注射3天）可减少LPS诱导的细胞因子向循环中的释放、肾上腺醛固酮合成和释放以及环氧化酶-2和IL-6基因表达。坎地沙坦不能预防LPS诱导的ACTH和皮质酮释放。我们的结果表明，1型受体对于对细菌内毒素产生完整的先天性免疫和应激反应至关重要。ARB减少了对LPS的全身性外周炎症反应，部分降低了肾上腺的炎症反应，阻止了促炎激素醛固酮的释放，并保护了糖皮质激素释放的抗炎作用。对细菌内毒素不受限制的先天性免疫反应可能对机体产生有害影响，并可能导致慢性炎症性疾病的发生。我们推测ARB可能对炎症性疾病具有治疗作用。
