Fibrosis involving the airways, vasculature, alveoli, and pleura is seen, to varying degrees, in a number of clinical syndromes, including asthma, subphenotypes of chronic obstructive pulmonary disease, pulmonary hypertension, and idiopathic pulmonary fibrosis (IPF). Currently, there are no FDA-approved anti-fibrotic therapies for any of these disorders in the United States. A common feature of fibrosis in these clinical-pathological contexts is the activation of tissue myofibroblasts. In this translational Program Project Grant (tPPG) application, we propose to develop pharmacologic strategies and agents targeting the myofibroblast in the most enigmatic and fatal form of pulmonary fibrosis, IPF. Current paradigms of the origin(s) of myofibroblasts posit that these fibrogenic cells derive from resident mesenchymal progenitors, alveolar epithelial cells (via epithelial-to-mesenchymal transition), or circulating fibrocytes. In this tPPG, we will investigate the role of pleural mesothelial cells (PMCs) as progenitors of activated lung myofibroblasts (Project 1). While myofibroblasts are widely considered a specific subset of a heterogeneous fibroblast population, in reality, they themselves manifest a number of different phenotypes, including migration/invasion, proliferation, contractility and apoptosis-resistance. Maintenance of myofibroblast differentiation and activation is governed by extracellular factors (matrix stiffness activation of latent TGF-?), cell adhesion/contractile factors (integrins, RhoA), and intracellular signaling cascades (SMAD2/3, Wilm's tumor-1) that activate or repress fibrogenic gene expression. These interacting pathways are controlled by the anti-fibrotic micro-RNA, miR-31, and the pro-fibrotic oxidant-generating enzyme, NADPH oxidase-4 (NOX4). This tPPG will establish proof-of-concept and provide essential pre-clinical data supporting the therapeutic efficacy of reconstituting miR-31 and/or inhibiting the expression/activation of N0X4 in experimental animal models and in cell/tissues of patients with IPF, leading rapidly to Phase l/ll clinical trials for this recalcitrant lung disease.

Public Health Relevance

IPF is fatal lung disorder for which no U.S. FDA-approved drugs currently exist. This project will lead to the development of novel anti-fibrotic therapies, which if proven effective, may also be tested in other clinical disorders characterized by myofibroblast activation and progressive fibrosis. (End of Abstract) PROJECT 1: ACTIVATION OF THE PLEURAL MESOTHELIUM IN IPF (Antony, Veena) RESUME AND SUMMARY OF DISCUSSION: Project 1 was felt to address an important clinical problem, and have notable strengths in the project leader and environment. There was considerable discussion of the need for an expanded, mechanistic analysis of WT-1-mediated signaling that could influence various aspects of MMT pathobiology. While WT-1 seems to be a novel, potentially important regulator of TGF action on pleural mesothelial cells and exhibits PMC-specific expression, the proposed therapeutic agents (NOX4 inhibitor and miR-31) could indirectly influence MMT not necessarily accompanied by direct changes in WT-1 signaling. To properly account for possible negative outcomes after therapy would require a more complete understanding of WT-1 promoter regulation and down-stream signaling in PMCs as a consequence of altered WT-1 expression. There was agreement that Aim 4 studies should be expanded to include some of these unexplored issues. There also was general agreement that Dr. Antony made a strong effort to address reviewer concerns raised during the A0 review and that the addition of an expert in 3D imaging (Dr. Soni) and the markedly improved Aim 2 were clear strengths. Overall this project was rated as outstanding. DESCRIPTION (as provided by applicant): IPF is a devastating disease characterized by the development of pulmonary fibrosis which starts in the subpleural region. Myofibroblasts populate the lung parenchyma in patients with IPF. However, their origin remains unclear. The pleural mesothelium derived from the mesoderm lines the lung and expresses the Wilms tumor gene (Wt1). In recent studies we have demonstrated that pleural mesothelial cells can differentiate into myofibroblasts and that pleural mesothelial cells are found in the lung parenchyma of patients with IPF. We hypothesize that pleural mesothelial cells (PMCs) contribute to the myofibroblast population in animal models of fibrogenic lung injury and in human IPF. In collaboration with the other projects in this proposal we will examine our hypothesis in the following specific aims: 1. Determine if PMCs traffic into the lung to form myofibroblasts in animal models of fibrogenic lung injury. 2. Determine the spatial profusion of PMCs in the lung parenchyma of IPF patients in histopathological 3D reconstruction studies and correlate with severity and/or progression of lung fibrosis. 3. Determine the regulatory role of Wt1 in the contractile, migratory and fibrogenic activities of normal and IPF-derived PMCs. 4. Determine if small molecule inhibitor, GKT137831 and/or miR-31 delivered via the intra-pleural route protects against fibrosis in murine models of fibrosis Using a cre-lox system for lineage tracing of PMCs, we will examine the role of PMCs in IPF and the contribution of Wt1 in modulating migration and differentiation of myofibroblasts. Using human cells and tissue, we will determine the role of IPF-PMCs in the pathology of IPF. These studies will stimulate new paradigms in IPF and define the contribution of the pleural mesothelium to lung parenchymal fibrosis. Local intrapleural delivery of small molecules targeting novel pathways will advance our development of directed therapeutics against IPF. PUBLIC HEALTH RELEVANCE: These studies will stimulate new concepts in IPF and define the contribution of the pleural mesothelium to lung parenchymal fibrosis. New paradigms including intrapleural delivery of therapeutic molecules targeting the pleural mesothelium will be evaluated. (End of Abstract)

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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Special Emphasis Panel (ZHL1-CSR-Q (M1))
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Eu, Jerry Pc
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University of Alabama Birmingham
Internal Medicine/Medicine
Schools of Medicine
United States
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