Attenuation of bleomycin-induced pulmonary fibrosis by follistatin

Am J Respir Crit Care Med. 2005 Sep 15;172(6):713-20. doi: 10.1164/rccm.200412-1620OC. Epub 2005 Jun 23.


Rationale: Activins are members of the transforming growth factor-beta superfamily thought to be involved in repair processes after tissue injury.

Objectives: The aim of this study was to clarify whether activin and its antagonist, follistatin, played a significant role in lung injury and fibrosis.

Methods and results: In bleomycin (BLM)-treated rat lung, mRNA for the beta(A) subunit of activin was upregulated on Days 3 and 7 and decreased gradually thereafter. Immunoreactive activin A was abundantly expressed in macrophages infiltrated in the lung, and was detected in fibroblasts accumulated in the fibrotic area on Day 28. We then administered follistatin, an activin antagonist, to BLM-treated rats. Follistatin significantly reduced the number of macrophages and neutrophils in bronchoalveolar lavage and reduced the protein content. Histologically, follistatin markedly reduced the number of infiltrating cells, ameliorated the destruction of lung architecture on Day 7, and attenuated lung fibrosis on Day 28. The hydroxyproline content was significantly lower in follistatin-treated rats. In cultured lung fibroblasts, production of activin A was augmented by transforming growth factor-beta, and activin antagonist follistatin significantly inhibited transforming growth factor-beta-induced fibroblast activation. These results suggest that activin A was produced in the lung after BLM treatment and promoted acute inflammation and subsequent fibrosis.

Conclusions: Follistatin is effective in treating acute lung injury and BLM-induced fibrosis by blocking the actions of activin and transforming growth factor-beta.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activin Receptors / metabolism
  • Activins / antagonists & inhibitors*
  • Activins / metabolism*
  • Animals
  • Bleomycin*
  • Cell Differentiation / drug effects
  • Cells, Cultured
  • Collagen / biosynthesis
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Fibroblasts / pathology
  • Follistatin / metabolism
  • Follistatin / pharmacology*
  • Humans
  • Inhibin-beta Subunits / antagonists & inhibitors*
  • Inhibin-beta Subunits / metabolism*
  • Lung / drug effects
  • Lung / metabolism
  • Lung / pathology
  • Pulmonary Fibrosis / chemically induced*
  • Pulmonary Fibrosis / metabolism
  • Pulmonary Fibrosis / pathology*
  • Rats
  • Rats, Wistar
  • Recombinant Proteins / pharmacology
  • Transforming Growth Factor beta / antagonists & inhibitors
  • Transforming Growth Factor beta / pharmacology
  • Up-Regulation


  • Follistatin
  • Recombinant Proteins
  • Transforming Growth Factor beta
  • activin A
  • Activins
  • Bleomycin
  • Collagen
  • Inhibin-beta Subunits
  • Activin Receptors