Idiopathic pulmonary fibrosis (IPF) is a devastating disease with less than a 50% five-year survival. While steroids and other immunosuppressive agents serve as the standard treatment for IPF, these agents have proved inadequate and have adverse side effects. Recent studies have identified hepatocyte growth factor (HGF) as an antifibrogenic agent that protects against liver and lung fibrosis in several animal models. The observation that HGF specifically stimulates growth of bronchial epithelial cells without inducing fibroblast replication suggests that HGF-based therapies could be more effective in the treatment of pulmonary fibrosis. In order to overcome the shortcomings and expense of protein therapy, we have developed a small molecule mimetic of HGF activity that was rationally designed through a novel combination of phage display and molecular modeling technology. In vitro, our lead HGF mimetic, Refanalin, activates the HGF receptor, c-Met, and induces its biological functions including activation of endothelial and bronchial epithelial cell proliferation, and inhibition of collagen mRNA synthesis and liver fibrosis in vivo. Recent studies suggest that Refanalin increases fibrinolytic potential by inducing cell surface plasmin generation in vitro, and decreases collagen content in bleomycin-induced pulmonary fibrosis in vivo. Quantitative histological evaluation demonstrated that Refanalin-treated lung sections have reduced interstitial fibrosis, alveolar apoptosis, and damaged tissue compared with the vehicle-treated group. In the proposed studies, we will further evaluate the protective effects of Refanalin on lung from pulmonary fibrosis animal models and explore the potential mechanisms involved in inducing anti fibrotic pathways, and the fibrinolytic potential in reducing lung fibrosis. The goal of our research is to develop a novel therapeutic strategy to inhibit the progression of tissue fibrosis. These studies promise to provide fundamental, preclinical information about the feasibility and efficacy of Refanalin as a new therapeutic approach for the treatment of pulmonary fibrosis. ? ?
