Mechanisms of Alveolar Epithelial Fluid Clearance

肺泡上皮液清除机制

• 批准号: 7047747
• 负责人: MICHAEL A. MATTHAY
• 金额: $ 33.29万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-12-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7047747
• 关键词: biological fluid transport; chloride channels; cyclic AMP; fibroblast growth factor; genetically modified animals; hyperoxia; laboratory mouse; laboratory rat; lung alveolus; lung injury; mitogens; nitric oxide; perfusion; pulmonary edema; respiratory epithelium; septicemia; sodium channel; sodium potassium exchanging ATPase; tissue /cell culture; vascular endothelial growth factors

DESCRIPTION (provided by applicant): The mechanisms that regulate alveolar epithelial salt and water transport, play a major role in determining lung fluid balance in patients with pulmonary edema and acute respiratory failure. Clinical studies have demonstrated that patients with impaired lung epithelial fluid transport have worse clinical outcomes. Although considerable progress has been made in understanding the basic salt and water transport mechanisms that regulate epithelial fluid transport in the lung, more work is needed to understand the cell specific and ion specific transporting function of the distal lung epithelium. In this renewal application, three aims are designed to identify new mechanisms that regulate fluid transport across the distal epithelium of the lung. Aim 1 will test the hypothesis that CFTR dependent chloride transport plays a major role in regulating cAMP mediated fluid clearance from the distal air spaces of lung. Using a novel in vitro epithelial fluid transport model, the experiments will test the role of CFTR in alveolar epithelial type I and type II cells as well as in an important distal airway epithelial cell, the Clara cell. Intact lung studies in CFTR deficient mice will also be done under pathologically relevant conditions (sepsis and hyperoxia). Aim 2 will examine how moderate hypoxia decreases fluid transport from the distal air spaces of the lung, testing the hypothesis that impaired trafficking of ENaC to the apical membrane and Na,K-ATPase subunits to the basolateral membrane of alveolar type II cells impairs fluid transport. This aim will also test the mechanism by which cAMP agonist therapy reverses the depressant effect of hypoxia on lung epithelial fluid clearance. Aim 3 will determine if endogenous production of nitric oxide downregulates cAMP stimulated epithelial fluid clearance in clinically relevant models of acute lung injury, including vascular endothelial growth factor induced pulmonary edema as well as in ventilator associated lung injury. Overall, these studies will provide important new insights into the basic mechanisms that regulate epithelial fluid transport and lung fluid balance in the normal and the injured lung.

描述（由申请人提供）：调节肺泡上皮盐和水运输的机制在确定肺水肿和急性呼吸衰竭患者的肺液平衡方面发挥着重要作用。 临床研究表明，肺上皮液体运输受损的患者临床结果较差。 尽管在了解调节肺内上皮液体运输的基本盐和水运输机制方面已经取得了相当大的进展，但还需要更多的工作来了解远端肺上皮的细胞特异性和离子特异性运输功能。 在这个更新应用中，设计了三个目标来确定调节穿过肺远端上皮的液体运输的新机制。 目标 1 将检验 CFTR 依赖性氯离子转运在调节 cAMP 介导的肺远端气腔液体清除中发挥重要作用的假设。 使用新型体外上皮液体转运模型，实验将测试 CFTR 在 I 型和 II 型肺泡上皮细胞以及重要的远端气道上皮细胞 Clara 细胞中的作用。 CFTR 缺陷小鼠的完整肺部研究也将在病理相关条件（败血症和高氧）下进行。 目标 2 将研究中度缺氧如何减少肺远端气腔的液体运输，检验以下假设：ENaC 向顶膜运输受损，Na,K-ATP 酶亚基向 II 型肺泡细胞基底外侧膜运输受损会损害液体运输。这一目标还将测试 cAMP 激动剂治疗逆转缺氧对肺上皮液体清除率的抑制作用的机制。 目标 3 将确定内源性一氧化氮的产生是否会下调 cAMP 刺激的急性肺损伤临床相关模型中的上皮液体清除率，包括血管内皮生长因子诱导的肺水肿以及呼吸机相关的肺损伤。 总的来说，这些研究将为调节正常和受损肺部的上皮液体运输和肺液体平衡的基本机制提供重要的新见解。