title: Inhibition of myocardin-related transcription factor/serum response factor signaling decreases lung fibrosis and promotes mesenchymal cell apoptosis.
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.
authors: 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.
authors: Thomas H
authors: TH
authors: Sisson
authors: Division of Pulmonary and Crucial Care Medicine, Department of Internal Medicine, College of Pharmacy, University of Michigan, Ann Arbor, Michigan.
authors: Iyabode O
authors: IO
authors: Ajayi
authors: Division of Pulmonary and Crucial Care Medicine, Department of Internal Medicine, College of Pharmacy, University of Michigan, Ann Arbor, Michigan.
authors: Natalya
authors: N
authors: Subbotina
authors: Division of Pulmonary and Crucial Care Medicine, Department of Internal Medicine, College of Pharmacy, University of Michigan, Ann Arbor, Michigan.
authors: Amos E
authors: AE
authors: Dodi
authors: Division of Gastroenterology, Medical School, College of Pharmacy, University of Michigan, Ann Arbor, Michigan.
authors: Eva S
authors: ES
authors: Rodansky
authors: Division of Pulmonary and Crucial Care Medicine, Department of Internal Medicine, College of Pharmacy, University of Michigan, Ann Arbor, Michigan.
authors: Lauren N
authors: LN
authors: Chibucos
authors: Division of Pulmonary and Crucial Care Medicine, Department of Internal Medicine, College of Pharmacy, University of Michigan, Ann Arbor, Michigan.
authors: Kevin K
authors: KK
authors: Kim
authors: Division of Pulmonary and Crucial Care Medicine, Department of Internal Medicine, College of Pharmacy, University of Michigan, Ann Arbor, Michigan.
authors: Venkateshwar G
authors: VG
authors: Keshamouni
authors: Division of Pulmonary and Crucial Care Medicine, Department of Internal Medicine, College of Pharmacy, University of Michigan, Ann Arbor, Michigan.
authors: Eric S
authors: ES
authors: White
authors: Division of Pulmonary, Allergy, and Critical Care, Department of Medicine, University of Alabama, Birmingham, Alabama.
authors: Yong
authors: Y
authors: Zhou
authors: Division of Gastroenterology, Medical School, College of Pharmacy, University of Michigan, Ann Arbor, Michigan.
authors: Peter D R
authors: PD
authors: Higgins
authors: Vahlteich Medicinal Chemistry Core, College of Pharmacy, University of Michigan, Ann Arbor, Michigan.
authors: Scott D
authors: SD
authors: Larsen
authors: Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan.
authors: Richard R
authors: RR
authors: Neubig
authors: 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.
authors: Jeffrey C
authors: JC
authors: Horowitz
mesh_terms: D000328:Adult; D056809:Alveolar Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D019610:Cytoprotection / Q000187:drug effects; D005353:Fibronectins / Q000378:metabolism; D005355:Fibrosis; D006801:Humans; D007249:Inflammation / Q000473:pathology; D008168:Lung / Q000378:metabolism* / Q000473:pathology*; D008648:Mesoderm / Q000187:drug effects / Q000473:pathology*; D008810:Mice, Inbred C57BL; D058628:Myofibroblasts / Q000473:pathology; D009557:Nipecotic Acids / Q000008:administration & dosage / Q000494:pharmacology; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D026362:Serum Response Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D034421:Sus scrofa; D015534:Trans-Activators / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism
chemical_list: C491901:FAS protein, human; D005353:Fibronectins; C431575:MRTFA protein, human; C511173:Mrtfa protein, mouse; C000589288:N-(4-chlorophenyl)-1-((3-(furan-2-yl)phenyl)carbonyl)piperidine-3-carboxamide; D009557:Nipecotic Acids; D017395:Plasminogen Activator Inhibitor 1; D026362:Serum Response Factor; D015534:Trans-Activators; D053773:Transforming Growth Factor beta1; D051636:X-Linked Inhibitor of Apoptosis Protein; D019014:fas Receptor