Effect of pirfenidone on rat hepatic stellate cell proliferation and collagen production

J Hepatol. 2002 Nov;37(5):584-91. doi: 10.1016/s0168-8278(02)00245-3.


Background/aims: Pirfenidone has been recently shown to reduce dimethynitrosamine-induced liver fibrosis in the rat, but no information are available on the effect of this drug on cultured hepatic stellate cells (HSC).

Methods: HSC proliferation was evaluated by measuring bromodeoxyuridine incorporation; PDGF-receptor autophosphorylation, extracellular signal-regulated kinase (ERK1/2) and pp70(S6K) activation were evaluated by western blot; protein kinase C activation was evaluated by western blot and by ELISA; type I collagen accumulation and alpha1(I) procollagen mRNA expression were evaluated by ELISA and northern blot, respectively.

Results: Pirfenidone significantly inhibited PDGF-induced HSC proliferation, starting at a concentration of 1 microM, with a maximal effect at 1000 microM, without affecting HSC viability and without inducing apoptosis. The inhibition of PDGF-induced HSC proliferation was associated neither with variations in PDGF-receptor autophosphorylation, or with ERK1/2 and pp70(S6K) activation. On the other hand, pirfenidone was able to inhibit PDGF-induced activation of the Na(+)/H(+) exchanger, which is involved in PDGF-induced HSC proliferation in HSC, with a maximal effect at 1000 microM and inhibited PDGF-induced protein kinase C activation. Pirfenidone 100 and 1000 microM inhibited type I collagen accumulation in the culture medium induced by transforming growth factor(beta1) by 54% and 92%, respectively, as well as TGF(beta1)-induced alpha1(I) procollagen mRNA expression.

Results: Pirfenidone could be a new candidate for antifibrotic therapy in chronic liver diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Cell Division / drug effects
  • Cells, Cultured
  • Collagen Type I / genetics*
  • Collagen Type I / metabolism
  • Culture Media / metabolism
  • Gene Expression / drug effects
  • Hepatocytes / cytology*
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism*
  • Male
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases / metabolism
  • Phosphorylation / drug effects
  • Platelet-Derived Growth Factor / pharmacology
  • Protein Kinase C / metabolism
  • Pyridones / pharmacology*
  • RNA, Messenger / analysis
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Platelet-Derived Growth Factor beta / metabolism
  • Ribosomal Protein S6 Kinases, 70-kDa / metabolism
  • Sodium-Hydrogen Exchangers / metabolism
  • Transforming Growth Factor beta / pharmacology
  • Transforming Growth Factor beta1


  • Antineoplastic Agents
  • Collagen Type I
  • Culture Media
  • Platelet-Derived Growth Factor
  • Pyridones
  • RNA, Messenger
  • Sodium-Hydrogen Exchangers
  • Tgfb1 protein, rat
  • Transforming Growth Factor beta
  • Transforming Growth Factor beta1
  • pirfenidone
  • Receptor, Platelet-Derived Growth Factor beta
  • Ribosomal Protein S6 Kinases, 70-kDa
  • ribosomal protein S6 kinase, 70kD, polypeptide 2
  • Protein Kinase C
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases