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，包括应激诱导型血红素加氧酶-1（HO-1）。 血红素加氧酶（HO）催化的第一个和限速步骤，在催化家庭产生等摩尔量的胆绿素IXa，一氧化碳（CO），和铁。 我们的实验室和其他实验室已经证明，HO-1的诱导在体内和体外都提供了细胞保护作用，以对抗氧化应激，包括但不限于高氧、缺血-再灌注和内毒素。 HO-1对氧化剂诱导的组织损伤提供细胞保护的机制知之甚少。 最近的研究强调了气体分子CO，HO活性的副产物，可以介导对氧化剂诱导的肺损伤的细胞保护的可能性。 此外，我们已经确定，CO介导的保护通过MKK 3/p38丝裂原活化激酶（MAPK）信号通路。 我们假设CO介导HO-1对内毒素休克的细胞保护作用，并且CO对p38 β和p38 β MAPK的相互作用介导促炎细胞因子TNF-α的相互下调和抗炎细胞因子IL-10的相互上调。 此外，我们假设NF-β B和NF-β依赖性gone iNOS之间复杂的相互作用调节CO诱导的p38活化及其功能性抗炎和细胞保护作用。 我们将通过以下目的来检验这一假设：1）鉴定哪些p38亚型（（，（）参与了用CO观察到的抗炎作用。2）确定NF-β B激活的作用和p38亚型在这种激活中的作用。 3)评价CO诱导的p38激活在内毒素休克中提供细胞保护的机制。 4)评估CO诱导的iNOS在细胞保护和诱导抗炎表型中的作用。

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.