Pirfenidone prevents endotoxin-induced liver injury after partial hepatectomy in rats.
OBJECTIVE
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-kappa B (NF-kappa B) 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 iNOS in part through the inhibition of NF-kappa B activation, resulting in the prevention of endotoxin-induced liver injury after hepatectomy.
Tsuchiya
Hideto
H
First Department of Surgery, Kansai Medical University, 10-15 Fumizonocho, Moriguchi, Osaka 570-8507, Japan.
Kaibori
Masaki
M
Yanagida
Hidesuke
H
Yokoigawa
Norio
N
Kwon
A-Hon
AH
Okumura
Tadayoshi
T
Kamiyama
Yasuo
Y
D000818:Animals; D019743:Chemokines, CXC / Q000037:antagonists & inhibitors; D016207:Cytokines / Q000037:antagonists & inhibitors; D019446:Endotoxemia / Q000150:complications*; D006498:Hepatectomy / Q000009:adverse effects* / Q000379:methods*; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors; D036341:Intercellular Signaling Peptides and Proteins; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008107:Liver Diseases / Q000209:etiology* / Q000517:prevention & control*; D008297:Male; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D009336:Necrosis; D020556:Neutrophil Infiltration / Q000187:drug effects; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D052247:Nitric Oxide Synthase Type II; D011728:Pyridones / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015996:Survival Rate; D014157:Transcription Factors / Q000037:antagonists & inhibitors
D019743:Chemokines, CXC; D016207:Cytokines; D018836:Inflammation Mediators; D036341:Intercellular Signaling Peptides and Proteins; D016328:NF-kappa B; D011728:Pyridones; D014157:Transcription Factors; C093844:pirfenidone; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat