Pathophysiology of Alveolar Epithelial Lung Injury - Project 2: Effects of Stretch on Alveolar Epithelial Cell Cytoskeleton

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 clinical