Injury to the lung occurring in such conditions as ARDS is associated with tissue remodeling that includes damage to pulmonary endothelium and epithelium with overgrowth of mesenchymal fibroblasts. Fibrotic diseases of the lung demonstrate a similar pattern. Angiotensin II (Ang II) plays an important role for mediating this process, while hepatocyte growth factor (HGF) is an endogenous factor, which participates in epithelial and endothelial repair and opposes fibrotic remodeling. The mechanism(s) of these events are largely unknown. The central hypothesis of this application is that HGF protects and repairs the lung through interfering with the production and actions of Ang II as well as by promoting epithelial and endothelial cell survival. The hypothesis has been formulated on the basis of strong preliminary data, which show that HGF inhibits the expression of angiotensin converting enzyme (ACE), the protease which proteolytically activates Ang II from Angiotensin I. HGF also attenuates Ang II- and bleomycin-induced cell death in lung epithelial and endothelial cells. The rationale for the proposed research is that, once knowledge of the mechanisms that are responsible for the protection and repair of the lung has been obtained, it will lead to new strategies that can be used to prevent and/or treat lung injury and fibrosis, thereby reducing the morbidity and mortality that are associated with these conditions. The central hypothesis will be tested and the objective of the application accomplished by pursuing two specific aims: 1) Characterize the mechanism by which HGF down regulates ACE gene expression, 2) Define signaling mechanisms of anti-apoptotic pathways regulated by HGF. It is my expectation that HGF suppresses the expression of ACE and inhibits Ang II-induced apoptosis via eliciting specific signal transduction events. These results will be significant because they are expected to provide new agents for preventative and therapeutic interventions for lung disease. In addition, it is expected that the results will fundamentally advance the field of lung cell biology.
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