Hepatic Ischemia/Reperfusion-Induced Lung Injury

描述（由申请人提供）： 这项独立科学家奖将提供受保护的研究时间， 使申请人能够发展和应用分子领域的新技能 生物学以及大大扩展了他的调查机制， 肝缺血/再灌注诱导肺损伤。 肝 缺血/再灌注是肝切除术的重要并发症 手术、移植、创伤和失血性休克，并且常常导致 急性肺损伤 肝脏缺血/再灌注的确切机制 肺损伤的原因目前尚不清楚。 我们的初步数据显示， 转录因子NF-κ B的激活发生在肺中， 肝再灌注和随后肝源性促炎性物质释放 细胞因子进入循环系统。 我们还提供了证据表明， 在肝缺血时，神经肽P物质增加， 再灌注 P物质是巨噬细胞的有效激活剂， 假设P物质响应肝脏缺血而释放 刺激肺泡巨噬细胞，促进肺诱导 炎症 这一建议将解决有关 缺血性肝损伤诱导急性肺炎症的机制 损伤 我们将确定转录的功能意义 NF-κ B在肝硬化致肺炎症反应中的作用 通过产生细胞可渗透的融合蛋白， NF-kB抑制剂IkBa的不可降解形式。 其次，我们将 确定肺泡巨噬细胞在肺部炎症反应中的作用 使用脂质体介导的消耗方法。 最后，我们将确定 P物质在肺炎症诱导中的病理生理作用 在肝缺血/再灌注后使用肽拮抗剂和/或突变体 缺乏P物质受体的小鼠。 研究将为新的治疗选择提供机制解释， 急性肺损伤，并可能适用于许多其他炎症 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.