Carbon monoxide protection against endotoxic shock involves reciprocal effects on iNOS in the lung and liver
Carbon monoxide protection against endotoxic shock involves reciprocal effects on iNOS in the lung and liver
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DOI：
10.1096/fj.03-0643fje
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发表时间：
2004-03-01
期刊：
影响因子：
4.8
通讯作者：
Otterbein, LE
中科院分区：
文献类型：
--
作者：
Sarady, JK;Zuckerbraun, BS;Otterbein, LE
一氧化碳（CO）最近出现具有强有力的细胞保护特性，这些影响的机制，但是，刚刚开始被阐明。在脂多糖（LPS）诱导的多器官功能衰竭的大鼠模型中，我们证明，暴露于低浓度的CO仅1小时赋予了一个有效的防御致命的内毒素血症，并有效地消除炎症反应。暴露于CO导致>80%的动物长期存活，而对照组为20%。在肺中，CO抑制LPS诱导的肺泡炎和相关的水肿形成，而在肝中，它降低血清丙氨酸转氨酶的表达，肝损伤的标志物。这种保护似乎部分基于肺和肝中的不同机制，其中CO对LPS诱导的iNOS表达和NO产生（对LPS的响应中的重要介质）具有相互作用。CO可抑制肺组织中iNOS和NO的表达，而增加肝组织中iNOS和NO的表达。原代肺巨噬细胞和肝细胞在体外的研究显示了类似的效果; CO抑制LPS诱导的细胞因子在肺巨噬细胞中的产生，同时减少LPS诱导的iNOS表达和亚硝酸盐积累，并保护肝细胞免于凋亡，同时增加iNOS表达。虽然目前还不清楚在何种程度上，这些变化在iNOS的贡献所赋予的CO的细胞保护，这是迷人的，在每个器官CO影响iNOS的方式是已知的保护在该器官：NO是治疗在肝脏，而它是在肺损伤。
Carbon monoxide (CO) has recently emerged as having potent cytoprotective properties; the mechanisms underlying these effects, however, are just beginning to be elucidated. In a rat model of lipopolysaccharide (LPS)-induced multiorgan failure, we demonstrate that exposure to a low concentration of CO for only 1 h imparts a potent defense against lethal endotoxemia and effectively abrogates the inflammatory response. Exposure to CO leads to long-term survival of >80% of animals vs. 20% in controls. In the lung, CO suppressed LPS-induced lung alveolitis and associated edema formation, while in the liver, it reduced expression of serum alanine aminotransferase, a marker of liver injury. This protection appears to be based in part on different mechanisms in the lung and liver in that CO had reciprocal effects on LPS-induced expression of iNOS and NO production, important mediators in the response to LPS. CO prevented the up-regulation of iNOS and NO in the lung while augmenting expression of iNOS and NO in the liver. Studies of primary lung macrophages and hepatocytes in vitro revealed a similar effect; CO inhibited LPS-induced cytokine production in lung macrophages while reducing LPS-induced iNOS expression and nitrite accumulation and protected hepatocytes from apoptosis while augmenting iNOS expression. Although it is unclear to which extent these changes in iNOS contribute to the cytoprotection conferred by CO, it is fascinating that in each organ CO influences iNOS in a manner known to be protective in that organ: NO is therapeutic in the liver while it is damaging in the lung.