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Pleural Mesothelial Cell Activation in Idiopathic Pulmonary Fibrosis FREE TO VIEW

Jason Zolak*, MD; Rajesh Jagirdar, BS; Ranu Surolia, PhD; Octavio Oliva, BS; Suman Karki, PhD; Victor John Thannickal, MD; Veena Antony, MD
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University of Alabama Birmingham, Birmingham, AL

Chest. 2012;142(4_MeetingAbstracts):953A. doi:10.1378/chest.1387544
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SESSION TYPE: New Insights into Idiopathic Pulmonary Fibrosis

PRESENTED ON: Sunday, October 21, 2012 at 01:15 PM - 02:45 PM

PURPOSE: Myofibroblast proliferation and extracellular matrix deposition with a subpleural distribution characterize idiopathic pulmonary fibrosis (IPF). Pleural mesothelial cell (PMC) myofibroblast transformation and haptotaxis occur in response to transforming growth factor-β1 (TGF-β1). PMCs are present in the lungs of IPF patients and correlate with disease severity. Heme oxygenase-1 (HO-1) catalyzes the degradation of heme into iron, biliverdin, and carbon monoxide (CO). CO and bilirubin prevent pulmonary fibrosis in animal models. We determined if HO-1 regulates PMC differentiation into myofibroblasts and parenchymal migration in IPF.

METHODS: Myofibroblast marker expression was measured in mouse PMCs treated with TGF-β1 with and without HO-1 inducers or CORM-2, a CO-releasing molecule. Contractility and haptotaxis assays were performed in normal PMCs and IPF PMCs treated with TGF-β1 with and without HO-1 inducers or CORM-2. Mice recombinant for green fluorescent protein (GFP) driven by the Wilms Tumor-1 (WT-1) promoter, a specific PMC marker, tracked PMC migration after intratracheal TGF-β1. Explanted human IPF lungs were stained for WT-1. Baseline HO-1 and myofibroblast marker expression and changes subsequent to TGF-β1 with and without treatment with HO-1 inducers or CORM-2 were measured in normal PMCs and IPF PMCs.

RESULTS: HO-1 induction and CORM-2 inhibit myofibroblast marker expression in mouse PMCs. HO-1 inducers and CORM-2 inhibit normal human PMC contractility and haptotaxis in response to TGF-β1. GFP-recombinant mice driven by the WT-1 promoter demonstrate GFP isolated to the pleura. 24 hours after intratracheal TGF-β1, GFP-positive cells migrate inside the lung with co-expression of alpha-smooth muscle actin. WT-1-positive cells are present within the lung parenchyma of patients with IPF. Hemin, an HO-1 inducer, and CORM-2 reversed the contractility and haptotaxis exhibited by IPF PMCs.

CONCLUSIONS: HO-1 regulates PMC differentiation into myofibroblasts and parenchymal migration in mice. Hemin and CORM-2 reverse the fibrotic disposition of PMCs from patients with IPF.

CLINICAL IMPLICATIONS: Intrapleural delivery of carbon monoxide-producing compounds may represent a novel treatment strategy in IPF by inhibiting PMC differentiation and parenchymal migration.

DISCLOSURE: The following authors have nothing to disclose: Jason Zolak, Rajesh Jagirdar, Ranu Surolia, Octavio Oliva, Suman Karki, Victor John Thannickal, Veena Antony

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University of Alabama Birmingham, Birmingham, AL




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