The activation of myofibroblast is a central feature of interstitial pulmonary fibrosis. The objective of this proposal is to examine the regulation of the lung myofibroblast phenotype with an emphasis on the signal transduction pathways utilized by these cells to increase matrix deposition. Following lung injury in vivo, fibroblasts in the interstitial wall display a myofibroblast phenotype with increased expression of alpha-smooth muscle actin and alpha1(I) collagen mRNA. We have shown that prostaglandin E2 (PGE2) down-regulated steady state levels for alpha1(I) collagen, connective tissue growth factor and alpha- smooth muscle actin mRNA. PGE2 also stimulated Ca2+ activated K+ channels that decrease cell volume, and sensitized the cells to death receptor mediated apoptosis. These results indicate that PGE2 inhibits expression of the myofibroblast phenotype and has significant anti-fibrogenic properties. Preliminary data indicate that treatment of fibroblasts with PGE2 causes decreases in phosphatidylinositiol 3-kinase (PI-3K) as assessed by levels of phosphorylated protein kinase B/Akt. Employing inhibitors to PI-3K and mutant Akt constructs, we find that the activity of the PI-3K system regulates the stability of the alpha1(I) collagen mRNA. We hypothesize that fibroblast activation and the development of the myofibroblast phenotype involves an up- regulation in the activity of the PI-3K signal transduction pathways which in turn up-regulates alpha1(I) collagen and alpha- smooth muscle actin mRNA expression. PGE2 down-regulates these processes by affecting PI-3K activity and decreasing cell hydration. We plan to use cellular and molecular approaches to test our hypothesis in vitro and in vivo. Our studies will provide new insights into the regulation of the myofibroblast and suggest new therapeutic options for the treatment of pulmonary fibrosis.
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