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

• Published in: Journal of hepatology 2002-11, Vol.37 (5), p.584-591
• Main Authors: Di Sario, Antonio, Bendia, Emanuele, Svegliati Baroni, Gianluca, Ridolfi, Francesco, Casini, Alessandro, Ceni, Elisabetta, Saccomanno, Stefania, Marzioni, Marco, Trozzi, Luciano, Sterpetti, Paola, Taffetani, Silvia, Benedetti, Antonio
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Biological and medical sciences; Cell Division - drug effects; Cells, Cultured; Collagen Type I - genetics; Collagen Type I - metabolism; Culture Media - metabolism; Digestive system; Gene Expression - drug effects; Hepatic fibrosis; Hepatocytes - cytology; Hepatocytes - drug effects; Hepatocytes - metabolism; Male; Medical sciences; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases - metabolism; Na +/H + exchanger; Pharmacology. Drug treatments; Phosphorylation - drug effects; Pirfenidone; Platelet-derived growth factor; Platelet-Derived Growth Factor - pharmacology; Protein Kinase C - metabolism; Pyridones - pharmacology; Rats; Rats, Sprague-Dawley; Receptor, Platelet-Derived Growth Factor beta - metabolism; Ribosomal Protein S6 Kinases, 70-kDa - metabolism; RNA, Messenger - analysis; Sodium-Hydrogen Exchangers - metabolism; Transforming Growth Factor beta - pharmacology; Transforming Growth Factor beta1; Transforming growth factor- β1
• ISSN: 0168-8278; 1600-0641
• 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 α1(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 μM, with a maximal effect at 1000 μM, 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 μM and inhibited PDGF-induced protein kinase C activation. Pirfenidone 100 and 1000 μM inhibited type I collagen accumulation in the culture medium induced by transforming growth factor β1 by 54% and 92%, respectively, as well as TGF β1-induced α1(I) procollagen mRNA expression. Results: Pirfenidone could be a new candidate for antifibrotic therapy in chronic liver diseases.