Pathophysiology of Alveolar Epithelial Lung Injury

描述（由申请人提供）： 该项目资助申请是建立在肺泡上皮细胞屏障的损伤和恢复在决定急性呼吸窘迫综合征（ARDS）患者的结局方面至关重要的假设之上的。在这些患者中，肺泡上皮的不同区域暴露于缺氧、高氧、拉伸和机械剪切，所有这些都可能导致肺泡上皮细胞损伤。我们已经组建了一个高度互动的高级研究人员小组，通过五个相互关联的项目来研究这些模型中的肺泡上皮细胞损伤。在项目1中，我们将确定缺氧通过磷酸化-内吞作用和泛素化-Na+泵降解抑制Na，K-ATP酶的机制，从而导致肺液体清除受损。在项目#2中，我们将确定肺泡上皮细胞暴露于周期性拉伸或周期性剪切应力通过改变中间丝（构成细胞骨架的主要蛋白质）的结构和功能而导致损伤的机制。在项目#3中，我们将确定细胞表面的层粘连蛋白和整合素作为机械信号分子在周期性拉伸过程中转导肺泡上皮细胞中MAPK信号的机制。在项目#4中，我们将研究受体依赖性和肺泡依赖性肺泡上皮细胞凋亡在高氧暴露后肺损伤发展中的作用。在项目5中，我们将确定上皮细胞暴露于周期性牵张增强基因转移到肺泡上皮的机制。对每个项目都进行了合作研究，初步结果支持这一建议的可行性。该计划项目的重点是在临床相关模型中阐明导致肺上皮细胞损伤的机制的组装研究人员的多学科专业知识。这些项目在概念上和实际上是互动的，项目的总和大于其部分的总和。收集的数据将提供一个主要肺泡上皮细胞蛋白质调节的综合图片（Na，K-ATP酶和中间丝代表总肺泡上皮细胞蛋白的约60%），决定了上皮细胞凋亡在肺损伤发病机制中的作用，制定新的战略，病毒将基因递送到肺，并确定细胞外基质在肺泡上皮细胞中的机械信号传导中的作用。从这些研究产生的数据中获得的见解将为开发治疗肺损伤患者的新治疗策略提供新的分子靶点。

DESCRIPTION (provided by applicant): This Program Project Grant application is founded on the hypothesis that the injury and recovery of the alveolar epithelial cell barrier are of crucial importance in determining the outcome of patients with the acute respiratory distress syndrome (ARDS). In these patients, different regions of the alveolar epithelium are exposed to hypoxia, hyperoxia, stretch and mechanical shear, all of which may contribute to alveolar epithelial cell injury. We have assembled a highly interactive group of senior investigators to study alveolar epithelial cell injury in these models via five interrelated projects. In Project # 1 we will determine the mechanisms by which hypoxia inhibits the Na,K-ATPase via phosphorylation-endocytosis and ubiquitination-degradation of the Na+ pump resulting in impaired lung liquid clearance. In Project # 2 we will determine the mechanisms by which exposure of alveolar epithelial cells to cyclic stretch or cyclic shear stress causes injury by altering the structure and function of intermediate filaments, the major protein comprising the cell cytoskeleton. In Project # 3 we will determine the mechanisms by which laminins and integrins at the cell surface serve as mechanosignaling molecules transducing MAPK signals in alveolar epithelial cells during cyclic stretch. In Project #4 we will investigate the role of receptor-dependent and mitochondrial-dependent alveolar epithelial apoptosis in the development of lung injury following exposure to hyperoxia. In Project # 5 we will determine the mechanisms by which exposure of epithelial cells to cyclic stretch enhances gene transfer to the alveolar epithelium. Collaborative studies have been conducted for each of the projects and the preliminary results support the feasibility of this proposal. This Program Project focuses the multidisciplinary expertise of the assembled investigators on the elucidation of mechanisms contributing to lung epithelial cell injury in clinically relevant models. These projects are interactive conceptually and pragmatically, where the aggregate of the projects is greater than the sum of its parts. The collective data will provide a composite picture of the regulation of the major alveolar epithelial cell proteins (the Na,K-ATPase and intermediate filaments represent about 60% of total alveolar epithelial cell proteins), determine the role of epithelial apoptosis in the pathogenesis of lung injury, develop novel strategies for the non-viral delivery of genes to the lung and define the role of the extracellular matrix in mechanosignaling in the alveolar epithelium. The insights gained from the data generated from these studies will provide novel molecular targets for the development of new therapeutic strategies to treat patients with lung injury.