Centrally administered lipopolysaccharide elicits sympathetic excitation via NAD(P)H oxidase-dependent mitogen-activated protein kinase signaling.
Centrally administered lipopolysaccharide elicits sympathetic excitation via NAD(P)H oxidase-dependent mitogen-activated protein kinase signaling.
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DOI：
10.1097/hjh.0b013e3283358b6e
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发表时间：
2010-04
影响因子：
4.9
通讯作者：
Felder RB
中科院分区：
文献类型：
--
作者：
Zhang ZH;Yu Y;Wei SG;Felder RB
炎症在心力衰竭和高血压中激活交感神经驱动的机制仍不明确。在本研究中，在脑室内注射脂多糖（LPS）来诱导细胞因子和其他炎症介质在脑内的表达，在没有其他兴奋介质的情况下，并使用ICV注射阻断或抑制剂来检测导致交感神经激活的下游信号通路。麻醉大鼠ICV注射LPS（5µg）可显著提高肾交感神经活性、血压和心率（p<0.05）。LPS增加了下丘脑NAD(p)H氧化酶亚基p47 phox和gp91phox mRNA表达量（p<0.05）、NAD(p)H氧化酶依赖性超氧化物生成量、下丘脑肿瘤坏死因子(TNF)-α、环氧化酶-2 (COX-2) mRNA表达量以及脑脊液（CSF） TNF-α和前列腺素E2 (PGE2) mRNA表达量。下丘脑室旁核超氧化物表达和c-Fos活性（表明神经元兴奋）双氢乙酯染色增加。超氧化物清扫剂tempol显著（p<0.05）降低了炎症介质的表达，降低了室旁核超氧化物的表达和神经元兴奋。SB203580 （p38丝裂原活化蛋白激酶抑制剂）也降低了下丘脑和脑脊液中炎症介质的表达。Tempol、apocynin （NAD(P)H氧化酶抑制剂）、SB203580和NS398 （COX-2抑制剂）均能降低CSF PGE2和对LPS的交感神经兴奋反应。LPS还增加了血管紧张素II型1受体mRNA，这一反应被罗布麻素和tempol阻断，但不被SB203580阻断。这些发现表明，在病理生理条件下，中枢炎症通过NAD(P) h -氧化酶和p38丝裂原激活的蛋白激酶依赖的PGE2合成激活交感神经系统。
The mechanisms by which inflammation activates sympathetic drive in heart failure and hypertension remain ill-defined. In this study, an intracerebroventricular (ICV) injection of lipopolysaccharide (LPS) was used to induce the expression of cytokines and other inflammatory mediators in the brain, in the absence of other excitatory mediators, and the downstream signaling pathways leading to sympathetic activation were examined using ICV injections of blocking or inhibiting agents. In anesthetized rats, ICV injection of LPS (5 µg) increased (p<0.05) renal sympathetic nerve activity, blood pressure and heart rate. LPS increased (p<0.05) hypothalamic mRNA for NAD(P)H oxidase subunits p47 phox and gp91phox, NAD(P)H-oxidase-dependent superoxide generation, hypothalamic mRNA for tumor necrosis factor (TNF)-α, cyclooxygenase-2 (COX-2), and cerebrospinal fluid (CSF) levels of TNF-α and prostaglandin E2 (PGE2). In the paraventricular nucleus of hypothalamus, dihydroethidium staining for superoxide expression and c-Fos activity (indicating neuronal excitation) increased. The superoxide scavenger tempol significantly (p<0.05) diminished the expression of inflammatory mediators, as well as superoxide expression and neuronal excitation in paraventricular nucleus. SB203580 (p38 mitogen-activated protein kinase inhibitor) also reduced the expression of inflammatory mediators in hypothalamus and CSF. Tempol, apocynin (NAD(P)H oxidase inhibitor), SB203580 and NS398 (COX-2 inhibitor) all reduced CSF PGE2 and the sympatho-excitatory response to LPS. LPS also increased angiotensin II type 1 receptor mRNA, a response blocked by apocynin and tempol but not by SB203580. These findings suggest that central inflammation in pathophysiological conditions activates the sympathetic nervous system via NAD(P)H-oxidase and p38 mitogen-activated protein kinase dependent synthesis of PGE2.