Anti-Inflammatory Effects of Carbon Monoxide in the Lung

描述（由申请人提供）：肺对氧化应激的细胞和分子反应涉及抗氧化酶和应激反应基因的表达增加，包括应激诱导的去氧血红素氧化酶-1 （HO-1）。血红素加氧酶（HO）催化分解代谢的第一步和限速步骤，产生等量的胆绿素IXa，一氧化碳（CO）和铁。我们的实验室和其他人已经证明，HO-1的诱导在体内和体外都能提供细胞保护，抵抗氧化应激，包括但不限于高氧、缺血再灌注和内毒素。HO-1对氧化诱导的组织损伤提供细胞保护的机制尚不清楚。最近的研究强调了气态分子CO的可能性，它是HO活性的副产物，可以介导细胞对氧化诱导的肺损伤的保护。此外，我们已经确定CO通过MKK3/p38丝裂原活化激酶（MAPK）信号通路介导保护。我们假设CO介导HO-1细胞对内毒素休克的保护作用，CO对p38(和p38（MAPK）的相互作用介导促炎细胞因子TNF-（）的相互下调和抗炎细胞因子IL-10的上调。此外，我们假设NF- B和NF- B依赖性去离子化iNOS之间的复杂相互作用调节co诱导的p38激活及其功能性抗炎和细胞保护作用。我们将通过解决以下目标来验证这一假设：1)确定哪些p38亚型((,（,（,()）参与了CO观察到的抗炎作用。2）确定NF- B激活的作用以及p38亚型在这一激活中的作用。3)评估co诱导的p38活化在内毒素休克中提供细胞保护的机制。4)评价co诱导的iNOS在细胞保护和抗炎表型诱导中的作用。

DESCRIPTION (provided by applicant): The cellular and molecular responses of the lung to oxidative stress involve increased expression of antioxidant enzymes and stress-response genes, including the stress-inducible gone heme oxygenase-1 (HO-1). Heme oxygenase (HO) catalyzes the first and rate-limiting step in the catabolism of home to yield equimolar quantities of biliverdin IXa, carbon monoxide (CO), and iron. Our laboratory and others have demonstrated that induction of HO-1 provides cytoprotection both in vivo and in vitro against oxidative stress including but not limited to hyperoxia, ischemia-reperfusion, and endotoxin. The mechanism(s) by which HO-1 provides cytoprotection against oxidant-induced tissue injury is poorly understood. Recent studies highlight the possibility that the gaseous molecule CO, a by-product of HO activity, can mediate cytoprotection against oxidant-induced lung injury. Furthermore, we have established that CO mediates protection via the MKK3/p38 mitogen-activated kinase (MAPK) signaling pathway. We hypothesize that CO mediates HO-1 cytoprotection against endotoxic shock and that the reciprocal effects exerted by CO on p38( and p38( MAPK mediate the reciprocal down-regulation of the pro-inflammatory cytokine TNF-( and the upregulation of the anti-inflammatory cytokine IL-10. Furthermore, we hypothesize that a complex interplay between NF-(B and the NF-(B-dependent gone iNOS regulates CO-induced p38 activation and its functional anti-inflammatory and cytoprotective effects. We will test this hypothesis by addressing the following aims: 1) to identify which of the p38 isoforms ((,(,(,() are involved in the anti-inflammatory effects observed with CO. 2) To determine the role of NF-(B activation and the role of the p38 isoforms in this activation. 3) Evaluate the mechanism by which CO-induced activation of p38 provides cytoprotection in endotoxic shock. 4) Evaluate the rote of CO-induced iNOS in the cytoprotection and induction of the anti-inflammatory phenotype.