Blocking follistatin-like 1 attenuates bleomycin-induced pulmonary fibrosis in mice

J Exp Med. 2015 Feb 9;212(2):235-52. doi: 10.1084/jem.20121878. Epub 2015 Jan 12.

Abstract

Progressive tissue fibrosis is a cause of major morbidity and mortality. Pulmonary fibrosis is an epithelial-mesenchymal disorder in which TGF-β1 plays a central role in pathogenesis. Here we show that follistatin-like 1 (FSTL1) differentially regulates TGF-β and bone morphogenetic protein signaling, leading to epithelial injury and fibroblast activation. Haplodeletion of Fstl1 in mice or blockage of FSTL1 with a neutralizing antibody in mice reduced bleomycin-induced fibrosis in vivo. Fstl1 is induced in response to lung injury and promotes the accumulation of myofibroblasts and subsequent fibrosis. These data suggest that Fstl1 may serve as a novel therapeutic target for treatment of progressive lung fibrosis.

Publication types

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

MeSH terms

  • Aged
  • Animals
  • Antibiotics, Antineoplastic / adverse effects
  • Antibodies, Monoclonal / pharmacology
  • Antibodies, Neutralizing / pharmacology
  • Bleomycin / adverse effects
  • Bone Morphogenetic Protein 4 / metabolism
  • Cell Communication
  • Cell Line
  • Disease Models, Animal
  • Female
  • Follistatin-Related Proteins / antagonists & inhibitors
  • Follistatin-Related Proteins / deficiency
  • Follistatin-Related Proteins / genetics*
  • Follistatin-Related Proteins / metabolism
  • Gene Expression
  • Humans
  • Inflammation / genetics
  • Inflammation / immunology
  • Inflammation / metabolism
  • Inflammation / pathology
  • Lung Injury / chemically induced
  • Lung Injury / genetics
  • Lung Injury / metabolism
  • Lung Injury / pathology
  • Male
  • Mesenchymal Stem Cells / metabolism
  • Mice
  • Mice, Knockout
  • Middle Aged
  • Myofibroblasts / immunology
  • Myofibroblasts / metabolism
  • Phenotype
  • Protein Binding
  • Pulmonary Fibrosis / chemically induced
  • Pulmonary Fibrosis / drug therapy
  • Pulmonary Fibrosis / genetics*
  • Pulmonary Fibrosis / metabolism
  • Respiratory Mucosa / immunology
  • Respiratory Mucosa / metabolism
  • Respiratory Mucosa / pathology
  • Signal Transduction
  • Smad Proteins / metabolism
  • Transforming Growth Factor beta1 / metabolism

Substances

  • Antibiotics, Antineoplastic
  • Antibodies, Monoclonal
  • Antibodies, Neutralizing
  • Bone Morphogenetic Protein 4
  • Follistatin-Related Proteins
  • Smad Proteins
  • Transforming Growth Factor beta1
  • Bleomycin
  • FSTL1 protein, human