Bilirubin inhibits iNOS expression and NO production in response to endotoxin in rats
Bilirubin inhibits iNOS expression and NO production in response to endotoxin in rats
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DOI：
10.1002/hep.20334
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发表时间：
2004-08-01
期刊：
影响因子：
13.5
通讯作者：
Zucker, SD
中科院分区：
文献类型：
--
作者：
Wang, WZW;Smith, DLH;Zucker, SD
血红素加氧酶（HO）的诱导型同工型HO-1在减轻组织损伤中起重要作用。由于HO-1催化胆红素合成的限速步骤，我们采用大鼠内毒素血症模型研究了胆红素是HO-1细胞保护的关键介质的假设。胆红素治疗可提高存活率，减轻脂多糖输注引起的肝损伤。血清NO和肿瘤坏死因子a水平。内毒素血症的关键介质和肝诱导型一氧化氮合酶（iNOS）表达在经胆红素处理的啮齿动物中显著低于对照动物。胆红素的腹腔内和局部给药也被发现可以改善由A-角叉菜胶注射引起的后爪炎症。与体内结果一致，胆红素显着抑制iNOS的表达和抑制NO的生产在脂多糖（LPS）刺激的RAW 264.7小鼠巨噬细胞。相比之下，胆红素治疗诱导LPS介导的前列腺素合成增加三倍，而环氧合酶表达或活性无显著变化，表明胆红素增强了类花生酸合成的底物可用性。胆红素对LPS介导的核因子κ B或p38丝裂原活化蛋白激酶的活化没有影响，这与核因子κ B非依赖性作用机制一致。总之，这些数据支持胆红素的细胞保护作用，其至少部分通过抑制iNOS表达以及潜在地通过刺激局部前列腺素E-2产生来介导。总之，我们的研究结果表明，胆红素的作用，软化组织损伤炎症刺激和支持的可能性，“黄疸败血症”的现象代表了适应性的生理反应内毒素血症。
The inducible isoform of heme oxygenase (HO), HO-1, has been shown to play an important role in attenuating tissue injury. Because HO-1 catalyzes the rate-limiting step in bilirubin synthesis, we examined the hypothesis that bilirubin is a key mediator of HO-1 cytoprotection, employing a rat model of endotoxemia. Bilirubin treatment resulted in improved survival and attenuated liver injury in response to lipopolysaccharide infusion. Serum levels of NO and tumor necrosis factor a. key mediators of endotoxemia, and hepatic inducible nitric oxide synthase (iNOS) expression were significantly lower in bilirubin-treated rodents versus control animals. Both intraperitoneal and local administration of bilirubin also was found to ameliorate hindpaw inflammation induced by the injection of A-carrageenan. Consistent with in vivo results, bilirubin significantly inhibited iNOS expression and suppressed NO production in lipopolysaccharide (LPS)-stimulated RAW 264.7 murine macrophages. In contrast, bilirubin treatment induced a threefold increase in LPS-mediated prostaglandin synthesis in the absence of significant changes in cyclooxygenase expression or activity, suggesting that bilirubin enhances substrate availability for eicosanoid synthesis. Bilirubin had no effect on LPS-mediated activation of nuclear factor kappaB or p38 mitogen-activated protein kinase, consistent with a nuclear factor kappaB-independent mechanism of action. Taken together, these data support a cytoprotective role for bilirubin that is mediated, at least in part, through the inhibition of iNOS expression and, potentially, through stimulation of local prostaglandin E-2 production. In conclusion, our findings suggest a role for bilirubin in mollifying tissue injury in response to inflammatory stimuli and support the possibility that the phenomenon of "jaundice of sepsis" represents an adaptive physiological response to endotoxemia.