Effect of pirfenidone on proliferation, TGF-β-induced myofibroblast differentiation and fibrogenic activity of primary human lung fibroblasts

Eur J Pharm Sci. 2014 Jul 16;58:13-9. doi: 10.1016/j.ejps.2014.02.014. Epub 2014 Mar 12.

Abstract

Pirfenidone is an orally active small molecule that has been shown to inhibit the progression of fibrosis in animal models and in patients with idiopathic pulmonary fibrosis. Although pirfenidone exhibits well documented antifibrotic and antiinflammatory activities, in vitro and in vivo, its molecular targets and mechanisms of action have not been elucidated. In this study, we investigated the effects of pirfenidone on proliferation, TGF-β-induced differentiation and fibrogenic activity of primary human lung fibroblasts (HLFs). Pirfenidone reduced fibroblast proliferation and attenuated TGF-β-induced α-smooth muscle actin (SMA) and pro-collagen (Col)-I mRNA and protein levels. Importantly, pirfenidone inhibited TGF-β-induced phosphorylation of Smad3, p38, and Akt, key factors in the TGF-β pathway. Together, these results demonstrate that pirfenidone modulates HLF proliferation and TGF-β-mediated differentiation into myofibroblasts by attenuating key TGF-β-induced signaling pathways.

Keywords: Fibrogenic activity; IPF; Lung fibroblasts; Pirfenidone; Proliferation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / genetics
  • Actins / metabolism
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Cell Differentiation / drug effects
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Cells, Cultured
  • Collagen Type I / genetics
  • Collagen Type I / metabolism
  • Fibroblasts / cytology
  • Fibroblasts / drug effects*
  • Fibroblasts / metabolism
  • Humans
  • Lung / cytology
  • Myofibroblasts / cytology
  • Myofibroblasts / drug effects
  • Myofibroblasts / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Pyridones / pharmacology*
  • Smad3 Protein / metabolism
  • Transforming Growth Factor beta
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • ACTA2 protein, human
  • Actins
  • Anti-Inflammatory Agents, Non-Steroidal
  • Collagen Type I
  • Pyridones
  • SMAD3 protein, human
  • Smad3 Protein
  • Transforming Growth Factor beta
  • collagen type I, alpha 1 chain
  • pirfenidone
  • Proto-Oncogene Proteins c-akt
  • p38 Mitogen-Activated Protein Kinases