Patients with pulmonary fibrosis develop significant dyspnea and debilitation. Most patients demonstrate significant progression of their disease and ultimately die of respiratory failure. Current therapy for pulmonary fibrosis is largely ineffective. While the exact mechanisms of fibrosis formation are unclear, fibroblasts are thought to play a central role in fibrosis development. Fibroblasts interact with fibronectin via both alpha 4 beta 1- and alpha 5 beta 1 - integrins. Data suggests that fibronectin signals through alpha 5 beta 1 to induce a cellular invasive phenotype, and through alpha 4 beta 1 to inhibit this phenotype. Therefore, the hypothesis of this proposal is that the invasive fibroblast phenotype in human pulmonary fibrosis is regulated by an imbalance in alpha 4 and alpha 5 integrin-mediated signaling; specifically, decreased alpha 4 expression or signaling is associated with an increase in fibroblast invasion of basement membranes. In vitro and in vivo studies will be performed to address the following Specific Aims: I) to demonstrate decreased alpha 4 integrin expression relative to alpha 5 integrin expression on human fibrotic-lung fibroblasts compared to normal human lung fibroblsts and establish that increased ivasion of basement membranes correlates with decreased alpha 4 integrin expression. II) to demonstrate that the increased basement membrane invasive activity of fibrotic-lung fibroblasts results from a deficiency in intracellular PTEN activity. III) to establish that fibroblastic foci from human specimens of pulmonary fibrosis display diminished PTEN expression compared to normal human lung fibroblasts in vivo, and IV) to demonstrate that restoration of alpha 4 beta 1 and alpha 5 beta 1 integrin signaling balance in vivo by blocking fibronectin stimulated alpha 5 beta 1 integrin signaling attenuates experimental pulmonary fibrosis. Successful completion of the studies outlined in this proposal may help to define mechanisms that lead to development of pulmonary fibrosis, and may lead to the identification of more effective and specific therapies to be employed in the treatment of patients with this disease.
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