Effects of pirfenidone on endotoxin-induced liver injury after partial hepatectomy in rats.
BACKGROUND
In living donor liver transplantation, restrictions on graft size are a serious obstacle to expand indications for adult recipients. The sequence of gram-negative infection, septicemia, and multiple-organ failure is a common cause of early mortality after liver transplantation. An effective therapy has not been established for endotoxemia following extended hepatectomy in donors or small-for-size grafts in recipients. Pirfenidone (PFD), a new experimental antifibrotic agent, was used to ameliorate on endotoxin-induced liver injury following partial hepatectomy.


METHODS
Male Sprague-Dawley rats were intravenously administered lipopolysaccharide (LPS) 48 hours after 70% hepatectomy. Prior to LPS administration, PFD (300 mg/kg) or its vehicle (0.5% carboxymethylcellulose) was given orally twice.


RESULTS
The survival rate of the PFD-treated group was markedly improved compared with that of the controls. PFD prevented the increases in the activities of serum enzymes (aspartate transaminase [AST], alanine transaminase [ALT], and lactate dehydrogenase [LDH]) and total bilirubin. The serum and liver tissue levels of inflammatory cytokines, such as tumor necrosis factor-alpha, interleukin-1beta, interferon-gamma, and interleukin-6, were significantly lower among the PFD than the control group. Furthermore, the degree of necrosis in the remnant liver was significantly decreased in the PFD-treated rats compared with controls.


CONCLUSIONS
These results indicate that PFD alleviates endotoxin-induced liver injury after partial hepatectomy through the inhibition of production of inflammatory cytokines in the residual liver. PFD may be useful to prevent endotoxin-induced liver injury after hepatectomy.
Kaibori
M
M
Department of Surgery, Kansai Medical University, Osaka, Japan. kaibori@takii.kmu.ac.jp
Yanagida
H
H
Yokoigawa
N
N
Hijikawa
T
T
Kwon
A-H
AH
Okumura
T
T
Kamiyama
Y
Y
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D004731:Endotoxins / Q000633:toxicity*; D006498:Hepatectomy; D008070:Lipopolysaccharides / Q000633:toxicity; D008099:Liver / Q000187:drug effects / Q000473:pathology*; D008111:Liver Function Tests; D008297:Male; D011728:Pyridones / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016019:Survival Analysis
D000894:Anti-Inflammatory Agents, Non-Steroidal; D004731:Endotoxins; D008070:Lipopolysaccharides; D011728:Pyridones; C093844:pirfenidone