Pleural mesothelial cell differentiation and invasion in fibrogenic lung injury.

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-β1 (TGF-β1) 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-β1. 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.

• Authors: Jason S Zolak, Rajesh Jagirdar, Ranu Surolia, Suman Karki, Octavio Oliva, Thomas Hock, Purushotham Guroji, Qiang Ding, Riu-Ming Liu, Subhashini Bolisetty, Anupam Agarwal, Victor J Thannickal, Veena B Antony
• Journal: The American journal of pathology (Am J Pathol) Vol. 182 Issue 4 Pg. 1239-47 (Apr 2013) ISSN: 1525-2191 [Electronic] United States
• PMID: 23399488 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, P.H.S.)
• Copyright: Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Chemical References

• 1-(2-cyano-3,12-dioxooleana-1,9-dien-28-oyl) imidazole
• Biomarkers
• Imidazoles
• Organometallic Compounds
• Transforming Growth Factor beta1
• tricarbonyldichlororuthenium (II) dimer
• Oleanolic Acid
• Hemin
• Carbon Monoxide
• Heme Oxygenase-1

Topics

• Administration, Inhalation
• Animals
• Biomarkers (metabolism)
• Carbon Monoxide (metabolism)
• Cell Differentiation (drug effects)
• Cell Movement (drug effects)
• Enzyme Induction (drug effects)
• Epithelial Cells (drug effects, enzymology, pathology)
• Heme Oxygenase-1 (biosynthesis, deficiency)
• Hemin (pharmacology)
• Humans
• Idiopathic Pulmonary Fibrosis (enzymology, pathology)
• Imidazoles (pharmacology)
• Lung (pathology)
• Lung Injury (enzymology, pathology)
• Mice
• Mice, Inbred C57BL
• Myofibroblasts (drug effects, metabolism, pathology)
• Oleanolic Acid (analogs & derivatives, pharmacology)
• Organometallic Compounds (pharmacology)
• Pleura (pathology)
• Transforming Growth Factor beta1 (pharmacology)