Acute Lung Injury (ALI) is a devastating syndrome with a mortality rate of 30-40 percent. Alveolar epithelial damage is a characteristic morphologic feature in patients with ALl. The loss of epithelial integrity contributes to the alveolar flooding and disrupts normal lung epithelial fluid transport that is important for the removal of pulmonary edema fluid from the airspaces. The molecular steps regulating the development and resolution of alveolar flooding in ALI are poorly understood. The cytokine transforming growth factor beta1 (TGF-beta1) plays a critical role in the resolution of ALI and in the development of lung fibrosis often associated with this syndrome. We previously reported that the expression levels of several TGF-beta1-inducible genes are dramatically increased early after the induction of experimental ALI induced with bleomycin. We also found the alpha-v-beta-6 integrin-mediated local activation of TGF-beta1 is critical to the development of pulmonary edema in ALI and that the activation of TGF-beta1 depends on a change in the conformation of the alpha-v-beta-6 integrin. However, the mechanism of activation of this integrin is still unknown. IL-1beta was found to be biologically active and primarily responsible for the inflammatory activity within the airspaces of patients with ALI. Moreover, transient overexpression of IL-1beta, but not of TNF-alpha, in the lung by adenoviral gene transfer was associated with progressive fibrotic changes and an increased expression of TGF-beta1. Finally, preliminary experiments from our laboratory indicate that IL-1beta, but not TNF-alpha, causes activation of the alpha-v-beta-6-mediated TGF-beta1-dependent cell signaling pathway in alveolar epithelial cells. Thus, this application will test the hypotheses that (a) the release of IL-1beta within the airspaces is responsible for the alpha-v-beta-6 integrin-mediated activation of TGF-beta1 (aim 1); (b) the activation of the focal adhesion kinase (FAK) and/or its downstream cell effectors, phosphoinositol-3-kinase and small GTPases, Rac-1 and RhoA, is required for IL-1beta-induced alpha-v-beta-6 integrin-mediated local activation of TGF-beta1 (aim 2); (c) locally activated TGF-beta1 decreases basal and c-AMP regulated lung epithelial fluid transport by altering the expression of amiloride-sensitive sodium channel, ENaC, on the cell membrane of lung epithelial cells (aim 3).
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