Regular article
Epithelial and mesenchymal cell biology
Pleural Mesothelial Cell Differentiation and Invasion in Fibrogenic Lung Injury

https://doi.org/10.1016/j.ajpath.2012.12.030Get rights and content
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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.

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Supported in part by National Institute for Occupational Safety and Health (NIOSH) grant 2T42OH008436 (J.S.Z.) and NIH grant R01AI080349 (V.B.A.).

J.S.Z. and R.J. contributed equally to this article.

Disclaimer: The contents are solely the responsibility of the authors and do not necessarily represent the official views of NIOSH.

No person at the University of Alabama at Birmingham was involved in the peer review process or final disposition for this article.