The avB6 integrin activates the fibrogenic cytokine, TGFB and is highly expressed in the epithelium of patients with Idiopathic Pulmonary Fibrosis. A blocking monoclonal antibody to this integrin effectively treats bleomycin and radiation-induced pulmonary fibrosis in mice, and a humanized version of this antibody is currently in phase 2 clinical trials. It would be desirably to target this pathway in patients, without the problems of antibody therapy or the risk of systemic side effects of blocking this integrin in unaffected organs. We and others have identified other av integrins that can activate TGFB, and these integrins might also play an important role in inducing fibrosis in the human lung. It would thus be desirable to be able to simultaneously target all of these integrins in patients with IPF. We have identified an absolute requirement for RhoA and its effector, Rho Kinase (ROCK) in avP6-mediated activation of TGFB. In the proposed studies we will first examine the effects of well-described small molecule inhibitors of ROCK and of of multiple av integrins that we have synthesized to inhibit pulmonary fibrosis in 4 different experiemental models in mice (induction of DNA damage and alveolar apoptosis by high dose bleomycin, induction of DNA damage combined with endoplasmic reticulum (ER) stress by low dose bleomycin and tunicamycin or by low dose bleomycin and expression of a surfactant protein C mutant, and induction of ER and lyosomal stress in a genetic model of the Hermansky Pudlak Syndrome). To minimize systemic toxicity, we will administer these drugs by aerosol and will then develop and test new small molecules based on these compounds that we have designed to increase hepatic metabolism and thus further reduce systemic toxicity. We will utilize BAL and blood samples from Core B to examine the potential of nriacrophage gene expression and SMAD2 phosphorylation, and secreted proteins identified as mechanistically informative biomarkers of this pathway in Core C to optimize a stategy for monitoring effective inhibition of this pathway in patients. Based on this work we expect to identify drugs to test in clinical trials in the second phase of this PPG and a greatly improved strategy for rapidly monitoring the effectiveness of these compounds in patients.
This project will develop new drugs to target a central step in the development of pulmonary fibrosis -activation of transforming growth factor beta. By targeting different steps in this process and modifying drugs for inhalation to maximize local effects while minimizing systemic side effects, we should greatly increase the likelihood of developing an effective and well tolerated treatment for this currently untreatable disease
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