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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Alveolar Epithelial Cells / drug effects
  • Alveolar Epithelial Cells / metabolism
  • Alveolar Epithelial Cells / pathology
  • Animals
  • Apoptosis* / drug effects
  • Cell Differentiation / drug effects
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism
  • Cytoprotection / drug effects
  • Fibronectins / metabolism
  • Fibrosis
  • Humans
  • Inflammation / pathology
  • Lung / metabolism*
  • Lung / pathology*
  • Mesoderm / drug effects
  • Mesoderm / pathology*
  • Mice, Inbred C57BL
  • Myofibroblasts / pathology
  • Nipecotic Acids / administration & dosage
  • Nipecotic Acids / pharmacology
  • Plasminogen Activator Inhibitor 1 / metabolism
  • Protein Transport / drug effects
  • Serum Response Factor / metabolism*
  • Signal Transduction* / drug effects
  • Sus scrofa
  • Trans-Activators / metabolism*
  • Transforming Growth Factor beta1 / pharmacology
  • X-Linked Inhibitor of Apoptosis Protein / metabolism
  • fas Receptor / metabolism


  • FAS protein, human
  • Fibronectins
  • MRTFA protein, human
  • Mrtfa protein, mouse
  • N-(4-chlorophenyl)-1-((3-(furan-2-yl)phenyl)carbonyl)piperidine-3-carboxamide
  • Nipecotic Acids
  • Plasminogen Activator Inhibitor 1
  • Serum Response Factor
  • Trans-Activators
  • Transforming Growth Factor beta1
  • X-Linked Inhibitor of Apoptosis Protein
  • fas Receptor