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Pleural mesothelial cell differentiation and invasion in fibrogenic lung injury.

Authors
Zolak-JS; Jagirdar-R; Surolia-R; Karki-S; Oliva-O; Hock-T; Guroji-P; Ding-Q; Liu-R-M; Bolisetty-S; Agarwal-A; Thannickal-VJ; Antony-VB
Source
Am J Pathol 2013 Apr; 182(4):1239-1247
NIOSHTIC No.
20043131
Abstract
The origin of the myofibroblast in fibrotic lung disease is uncertain, and no effective medical therapy for fibrosis exists. We have previously demonstrated that transforming growth factor-1 (TGF-1) induces pleural mesothelial cell (PMC) transformation into myofibroblasts and haptotactic migration in vitro. Whether PMC differentiation and migration occurs in vivo, and whether this response can be modulated for therapeutic benefit, is unknown. Here, using mice recombinant for green fluorescent protein (GFP) driven by the Wilms tumor-1 (WT-1) promoter, we demonstrate PMC trafficking into the lung and differentiation into myofibroblasts. Carbon monoxide or the induction of heme oxygenase-1 (HO-1) inhibited the expression of myofibroblast markers, contractility, and haptotaxis in PMCs treated with TGF-1. Intrapleural HO-1 induction inhibited PMC migration after intratracheal fibrogenic injury. PMCs from patients with idiopathic pulmonary fibrosis (IPF) exhibited increased expression of myofibroblast markers and enhanced contractility and haptotaxis, compared with normal PMCs. Carbon monoxide reversed this IPF PMC profibrotic phenotype. WT-1-expressing cells were present within fibrotic regions of the lungs in IPF subjects, supporting a role for PMC differentiation and trafficking as contributors to the myofibroblast population in lung fibrosis. Our findings also support a potential role for pleural-based therapies to modulate pleural mesothelial activation and parenchymal fibrosis progression.
Keywords
Respiratory-system-disorders; Pulmonary-system-disorders; Lung-disorders; Pleural-cavity; Mesothelial-cells; Fibrogenicity; Lung-cells; Lung-fibrosis; Growth-factors; Cell-transformation; Biomarkers; Laboratory-animals; Proteins; Tumor-inhibition; Cell-migration; Cellular-reactions; Therapeutic-agents; Cell-differentiation
Contact
Jason S. Zolak, M.D., Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, 1900 University Blvd., THT 422, Birmingham, AL 35294-0006
CODEN
AJPAA4
CAS No.
630-08-0
Publication Date
20130401
Document Type
Journal Article
Email Address
jasonzolak@gmail.com
Funding Type
Grant
Fiscal Year
2013
NTIS Accession No.
NTIS Price
Identifying No.
Grant-Number-T42-OH-008436; M102013
Issue of Publication
4
ISSN
0002-9440
Source Name
American Journal of Pathology
State
AL
Performing Organization
University of Alabama at Birmingham
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