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.
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.
|Huang, Wen-Tan; Akhter, Hasina; Jiang, Chunsun et al. (2015) Plasminogen activator inhibitor 1, fibroblast apoptosis resistance, and aging-related susceptibility to lung fibrosis. Exp Gerontol 61:62-75|
|Thannickal, Victor J; Zhou, Yong; Gaggar, Amit et al. (2014) Fibrosis: ultimate and proximate causes. J Clin Invest 124:4673-7|
|Xie, Na; Cui, Huachun; Banerjee, Sami et al. (2014) miR-27a regulates inflammatory response of macrophages by targeting IL-10. J Immunol 193:327-34|
|Desai, Leena P; Zhou, Yong; Estrada, Aida V et al. (2014) Negative regulation of NADPH oxidase 4 by hydrogen peroxide-inducible clone 5 (Hic-5) protein. J Biol Chem 289:18270-8|
|Blackwell, Timothy S; Tager, Andrew M; Borok, Zea et al. (2014) Future directions in idiopathic pulmonary fibrosis research. An NHLBI workshop report. Am J Respir Crit Care Med 189:214-22|
|Hu, Meng; Che, Pulin; Han, Xiaosi et al. (2014) Therapeutic targeting of SRC kinase in myofibroblast differentiation and pulmonary fibrosis. J Pharmacol Exp Ther 351:87-95|
|Bai, Guangxing; Hock, Thomas D; Logsdon, Naomi et al. (2014) A far-upstream AP-1/Smad binding box regulates human NOX4 promoter activation by transforming growth factor-?. Gene 540:62-7|
|Hecker, Louise; Logsdon, Naomi J; Kurundkar, Deepali et al. (2014) Reversal of persistent fibrosis in aging by targeting Nox4-Nrf2 redox imbalance. Sci Transl Med 6:231ra47|
|Cui, Huachun; Xie, Na; Tan, Zheng et al. (2014) The human long noncoding RNA lnc-IL7R regulates the inflammatory response. Eur J Immunol 44:2085-95|
|Karki, Suman; Surolia, Ranu; Hock, Thomas David et al. (2014) Wilms' tumor 1 (Wt1) regulates pleural mesothelial cell plasticity and transition into myofibroblasts in idiopathic pulmonary fibrosis. FASEB J 28:1122-31|
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