Pirfenidone prevents endotoxin-induced liver injury after partial hepatectomy in rats

Background/Aims: Massive liver resection causes a variety of complications including endotoxemia. Pirfenidone (PFD) is a new experimental drug used as antifibrotic agent. Studies were performed to investigate whether PFD influences the survival rate of animals with endotoxin-induced liver injury after partial hepatectomy, and the mechanisms involved. Methods: Rats were treated with lipopolysaccharide (LPS) 48 h after 70% hepatectomy. PFD was administered orally before LPS injection. Results: PFD improved the survival rate of LPS-treated rats after hepatectomy. PFD prevented increases in serum enzymes and total bilirubin related to liver injury. Histopathological analysis revealed that PFD inhibited the enhancement in hepatic necrosis and apoptosis. Further, PFD inhibited increases of inflammatory cytokines and cytokine-induced neutrophil chemoattractant (CINC) in serum and liver, followed by decreases of number of infiltrating neutrophils into liver. Electrophoretic mobility shift assay revealed that PFD inhibited the activation of transcription factor nuclear factor-kappaB (NF-kappaB) induced by LPS. PFD also reduced the induction of inducible nitric oxide synthase (iNOS) in the liver of LPS-treated rats. Conclusions: These results indicate that PFD inhibits the productions of inflammatory cytokines, CINC and NOS in part through the inhibition of NF-kappaB activation, resulting in the prevention of endotoxin-induced liver injury after hepatectomy. (C) 2003 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.