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 (Wtl). 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 Wtl 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 Wtl 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.

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These studies will simulate 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.

National Institute of Health (NIH)
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University of Alabama Birmingham
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