• Pirfenidone downregulates eIF6, P311, and TGF-β expression and improves liver fibrosis induced by Bile duct ligation in Wistar rats; evidence for liver regeneration
  • Zeynab Yousefi,1 Abbas Sahebghadam Lotfi,2,* Mitra Nourbakhsh,3
    1. Department of Clinical Biochemistry, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
    2. Department of Clinical Biochemistry, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
    3. Department of Clinical Biochemistry, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.


  • Introduction: liver fibrosis (LF) is a clinical disorder characterized by Inflammation and extra cellular matrix (ECM) accumulation. Pirfenidone (PFD) is an orally bioavailable pyridone derivative as well as a novel compound with anti-inflammatory and anti-fibrotic effects. The mechanism of its action remains uncertain. This study aims to investigate the influences of PFD on improving LF histologically and through modulation of eIF6, P311, and TGF-β in rats induced by Bile Duct Ligation (BDL).
  • Methods: Liver fibrosis was induced in Wistar rats using the BDL model. Animals received daily gavage administration of PFD (200 and 500 mg/kg) for 4 weeks. Liver index, hydroxyproline (Hyp) and ALT, AST, and ALP serum levels were calculated. Pathological changes in hepatic tissue were examined using histological staining with haematoxylin and eosin (H&E), Sirius red, and Masson’s trichrome staining, as well as immunohistochemical (IHC) analysis to monitor α-SMA and tissue repair markers (Ki-67 and HepPar-1). The mRNA levels of eIF6, P311, and TGF-β, as well as ECM deposition, HSC activation, and inflammatory mediator genes, were measured by RT-qPCR. We also monitored the protein levels of eIF6, P311, and TGF-β, which were detected by western blotting.
  • Results: Compared with the BDL group, PFD dose-dependently reduced Hyp, Liver index and the serum levels of ALT, AST, ALP in rats. Histological staining also showed that PFD reduced the fibrosis score and fibrosis area (40 and 50 percent in doses of 200 and 500 mg/kg respectively) in tissues. Additionally, PFD dose-dependently modulated BDL-induced hepatic inflammation, ECM accumulation, and HSC activation. Immunohistochemical staining of Ki-67 and HepPar-1 in hepatic tissue revealed that PFD enhanced liver regeneration. Besides, the research confirmed that PFD gradually downregulated elevated levels of eIF6, P311, and TGF-β in BDL-induced LF.
  • Conclusion: The findings suggest that PFD might be a potential treatment for LF. PFD can attenuate LF and enhance liver regeneration in a BDL-induced liver injury model, and this effect may be due to modulation of eIF6, P311 and TGF-β besides improvement in inflammatory response, HSC activation, ECM accumulation, and enhancing its degradation.
  • Keywords: Pirfenidone, Liver fibrosis, Bile duct ligation, eIF6, P311