title: 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: Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294-0006, USA. jasonzolak@gmail.com
authors: Jason S
authors: JS
authors: Zolak
authors: Rajesh
authors: R
authors: Jagirdar
authors: Ranu
authors: R
authors: Surolia
authors: Suman
authors: S
authors: Karki
authors: Octavio
authors: O
authors: Oliva
authors: Thomas
authors: T
authors: Hock
authors: Purushotham
authors: P
authors: Guroji
authors: Qiang
authors: Q
authors: Ding
authors: Riu-Ming
authors: RM
authors: Liu
authors: Subhashini
authors: S
authors: Bolisetty
authors: Anupam
authors: A
authors: Agarwal
authors: Victor J
authors: VJ
authors: Thannickal
authors: Veena B
authors: VB
authors: Antony
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002248:Carbon Monoxide / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D051547:Heme Oxygenase-1 / Q000096:biosynthesis / Q000172:deficiency; D006427:Hemin / Q000494:pharmacology; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000201:enzymology / Q000473:pathology*; D007093:Imidazoles / Q000494:pharmacology; D008168:Lung / Q000473:pathology; D055370:Lung Injury / Q000201:enzymology / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D058628:Myofibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009828:Oleanolic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D009942:Organometallic Compounds / Q000494:pharmacology; D010994:Pleura / Q000473:pathology*; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology
chemical_list: C472829:1-(2-cyano-3,12-dioxooleana-1,9-dien-28-oyl) imidazole; D015415:Biomarkers; D007093:Imidazoles; D009942:Organometallic Compounds; D053773:Transforming Growth Factor beta1; C447082:tricarbonyldichlororuthenium (II) dimer; D009828:Oleanolic Acid; D006427:Hemin; D002248:Carbon Monoxide; D051547:Heme Oxygenase-1
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