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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL114470-02
Application #
8735178
Study Section
Special Emphasis Panel (ZHL1)
Project Start
Project End
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Type
DUNS #
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Zhou, Yong; Horowitz, Jeffrey C; Naba, Alexandra et al. (2018) Extracellular matrix in lung development, homeostasis and disease. Matrix Biol 73:77-104
Cui, Huachun; Xie, Na; Banerjee, Sami et al. (2018) Impairment of Fatty Acid Oxidation in Alveolar Epithelial Cells Mediates Acute Lung Injury. Am J Respir Cell Mol Biol :
Hough, Kenneth P; Trevor, Jennifer L; Strenkowski, John G et al. (2018) Exosomal transfer of mitochondria from airway myeloid-derived regulatory cells to T cells. Redox Biol 18:54-64
Bernard, Karen; Logsdon, Naomi J; Benavides, Gloria A et al. (2018) Glutaminolysis is required for transforming growth factor-?1-induced myofibroblast differentiation and activation. J Biol Chem 293:1218-1228
Ge, Jing; Cui, Huachun; Xie, Na et al. (2018) Glutaminolysis Promotes Collagen Translation and Stability via ?-Ketoglutarate-mediated mTOR Activation and Proline Hydroxylation. Am J Respir Cell Mol Biol 58:378-390
Hough, Kenneth P; Wilson, Landon S; Trevor, Jennifer L et al. (2018) Unique Lipid Signatures of Extracellular Vesicles from the Airways of Asthmatics. Sci Rep 8:10340
Cui, Huachun; Banerjee, Sami; Guo, Sijia et al. (2018) IFN Regulatory Factor 2 Inhibits Expression of Glycolytic Genes and Lipopolysaccharide-Induced Proinflammatory Responses in Macrophages. J Immunol 200:3218-3230
Chanda, Diptiman; Otoupalova, Eva; Smith, Samuel R et al. (2018) Developmental pathways in the pathogenesis of lung fibrosis. Mol Aspects Med :
Qu, Jing; Zhu, Lanyan; Zhou, Zijing et al. (2018) Reversing Mechanoinductive DSP Expression by CRISPR/dCas9-mediated Epigenome Editing. Am J Respir Crit Care Med 198:599-609
Thannickal, Victor J; Antony, Veena B (2018) Is personalized medicine a realistic goal in idiopathic pulmonary fibrosis? Expert Rev Respir Med 12:441-443

Showing the most recent 10 out of 70 publications