Hepatic Ischemia/Reperfusion-Induced Lung Injury

肝缺血/再灌注引起的肺损伤

• 批准号: 6584706
• 负责人: Alex B. Lentsch
• 金额: $ 10.72万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6584706
• 关键词: I kappa B beta; Mammalia; alveolar macrophages; chimeric proteins; cytokine; inflammation; liposomes; liver ischemia /hypoxia; lung injury; nuclear factor kappa beta; reperfusion; substance P

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.

描述（由申请人提供）： 该独立科学家奖将为以下人员提供受保护的研究时间 使申请人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机制的研究 肝缺血/再灌注引起的肺损伤。 肝的 缺血/再灌注是肝切除术的一个重要并发症 手术、移植、创伤和失血性休克，通常会导致 急性肺损伤。 肝脏缺血/再灌注的精确机制 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 NF-kB 的激活先于肺部发生 肝再灌注和随后肝源性促炎物质的释放 细胞因子进入循环。 我们还提供证据表明血清水平 神经肽 P 物质在肝缺血期间增加 再灌注。 P 物质是巨噬细胞的有效激活剂，我们 假设 P 物质因肝缺血而释放 刺激肺泡巨噬细胞并促进肺的诱导 炎。 该提案将解决有关 缺血性肝损伤诱发急性肺部炎症的机制 受伤。 我们将确定转录的功能意义 NF-kB在肝脏诱导的肺部炎症反应中的作用 通过产生含有细胞渗透性的融合蛋白来实现缺血/再灌注 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物质在诱导肺部炎症中的病理生理作用 使用肽拮抗剂和/或突变体进行肝缺血/再灌注后 缺乏 P 物质受体的小鼠。从这些中获得的知识 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。