Hepatic Ischemia/Reperfusion-Induced Lung Injury

描述(由申请人提供)： 这一独立科学家奖将提供受保护的研究时间 使申请者能够开发和应用分子领域的新技能 生物学，并极大地扩展了他对 肝缺血/再灌注性肺损伤。肝脏 缺血/再灌流是肝切除的重要并发症 手术、移植、创伤和失血性休克，往往会导致 急性肺损伤。肝缺血/再灌流的确切机制 导致肺损伤的原因目前尚不清楚。我们的初步数据表明 转录因子核因子-kB的激活发生在肺组织中 肝脏再灌流和随后肝源性促炎因子的释放 细胞因子进入血液循环。我们还提供了证据表明血清中的 肝脏缺血期间神经肽P物质升高，在此之前 再灌流。P物质是巨噬细胞的有效激活剂，我们 肝缺血后P物质释放的假说 刺激肺泡巨噬细胞，促进肺的诱导 发炎。这项提案将解决有关 缺血性肝损伤诱导急性肺炎症的机制 受伤。我们将确定转录的功能意义 因子、核因子-kB在肝性肺炎性反应中的作用 通过产生细胞通透性融合蛋白来实现缺血/再灌注 非降解形式的核因子-kB抑制物IkBA。其次，我们将 确定肺泡巨噬细胞在肺炎性反应中的作用 使用脂质体介导的耗竭方法。最后，我们将确定 P物质在诱导肺部炎症中的病理生理作用 肝缺血/再灌注后应用多肽拮抗剂和/或突变体 缺乏P物质受体的小鼠从这些知识中获得 研究将为新的治疗方案提供机制解释 急性肺损伤，并可能适用于其他一些炎症性疾病 肺部疾病。

DESCRIPTION (provided by applicant): This Independent Scientist Award will provide protected research time to enable the applicant to develop and apply new skills in the area of molecular biology as well as greatly expand his investigations into the mechanisms of hepatic ischemia/reperfusion-induced lung injury. Hepatic ischemia/reperfusion is a significant complication of liver resectional surgery, transplantation, trauma and hemorrhagic shock, and often results in acute lung injury. The precise mechanisms by which liver ischemia/reperfusion causes lung injury are currently unknown. Our preliminary data suggest that activation of the transcription factor, NF-kB, occurs in the lung prior to hepatic reperfusion and subsequent release of liver-derived proinflammatory cytokines into the circulation. We also provide evidence that serum levels of the neuropeptide, substance P, increase during hepatic ischemia, prior to reperfusion. Substance P is a potent activator of macrophages and we hypothesize that substance P release in response to hepatic ischemia stimulates alveolar macrophages and promotes the induction of lung inflammation. This proposal will address fundamental questions about the mechanisms by which ischemic liver injury induces acute lung inflammatory injury. We will determine the functional significance of the transcription factor, NF-kB in the lung inflammatory response induced by hepatic ischemia/reperfusion by generating cell-permeable fusion proteins containing a non-degradable form of the inhibitor of NF-kB, IkBa. Secondly, we will determine the role of alveolar macrophages in this lung inflammatory response using liposome-mediated depletion methods. Finally, we will determine the pathophysiological role of substance P in the induction of lung inflammation after hepatic ischemia/reperfusion using peptide antagonists and/or mutant mice lacking the receptor for substance P. The knowledge gained from these studies will provide mechanistic explanations for new therapeutic options for acute lung injury, and may be applicable to a number of other inflammatory lung diseases.