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Am J Pathol. 2015 Apr;185(4):969-86. doi: 10.1016/j.ajpath.2014.12.005. Epub 2015 Feb 11.

Inhibition of myocardin-related transcription factor/serum response factor signaling decreases lung fibrosis and promotes mesenchymal cell apoptosis.

Author information

1
Division of Pulmonary and Crucial Care Medicine, Department of Internal Medicine, College of Pharmacy, University of Michigan, Ann Arbor, Michigan. Electronic address: tsisson@med.umich.edu.
2
Division of Pulmonary and Crucial Care Medicine, Department of Internal Medicine, College of Pharmacy, University of Michigan, Ann Arbor, Michigan.
3
Division of Gastroenterology, Medical School, College of Pharmacy, University of Michigan, Ann Arbor, Michigan.
4
Division of Pulmonary, Allergy, and Critical Care, Department of Medicine, University of Alabama, Birmingham, Alabama.
5
Vahlteich Medicinal Chemistry Core, College of Pharmacy, University of Michigan, Ann Arbor, Michigan.
6
Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan.
7
Division of Pulmonary and Crucial Care Medicine, Department of Internal Medicine, College of Pharmacy, University of Michigan, Ann Arbor, Michigan. Electronic address: jchorow@umich.edu.

Abstract

Myofibroblasts are crucial to the pathogenesis of tissue fibrosis. Their formation of stress fibers results in the release of myocardin-related transcription factor (MRTF), a transcriptional coactivator of serum response factor (SRF). MRTF-A (Mkl1)-deficient mice are protected from lung fibrosis. We hypothesized that the SRF/MRTF pathway inhibitor CCG-203971 would modulate myofibroblast function in vitro and limit lung fibrosis in vivo. Normal and idiopathic pulmonary fibrosis lung fibroblasts were treated with/without CCG-203971 (N-[4-chlorophenyl]-1-[3-(2-furanyl)benzoyl]-3-piperidine carboxamide) and/or Fas-activating antibody in the presence/absence of transforming growth factor (TGF)-β1, and apoptosis was assessed. In vivo studies examined the effect of therapeutically administered CCG-203971 on lung fibrosis in two distinct murine models of fibrosis induced by bleomycin or targeted type II alveolar epithelial injury. In vitro, CCG-203971 prevented nuclear localization of MRTF-A; increased the apoptotic susceptibility of normal and idiopathic pulmonary fibrosis fibroblasts; blocked TGF-β1-induced myofibroblast differentiation; and inhibited TGF-β1-induced expression of fibronectin, X-linked inhibitor of apoptosis, and plasminogen activator inhibitor-1. TGF-β1 did not protect fibroblasts or myofibroblasts from apoptosis in the presence of CCG-203971. In vivo, CCG-203971 significantly reduced lung collagen content in both murine models while decreasing alveolar plasminogen activator inhibitor-1 and promoting myofibroblast apoptosis. These data support a central role of the SRF/MRTF pathway in the pathobiology of lung fibrosis and suggest that its inhibition can help resolve lung fibrosis by promoting fibroblast apoptosis.

PMID:
25681733
PMCID:
PMC4380846
DOI:
10.1016/j.ajpath.2014.12.005
[Indexed for MEDLINE]
Free PMC Article

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