Selective suppression of initial cytokine response facilitates liver regeneration after extensive hepatectomy in rats.
OBJECTIVE
After extensive hepatectomy, the cytokine network plays an important role in injury to the remnant liver and subsequent impairment of liver regeneration. Tumor necrosis factor alpha (TNF alpha) and interleukin 1beta (IL-1beta) are thought to be the initial cytokines associated with liver injury as well as with regeneration. We investigated the effect of the suppression of these cytokines on liver function and on liver regeneration after subtotal hepatectomy in rats.


METHODS
Following 90% hepatectomy, rats were divided into two groups. Animals in the FR group received intraperitoneal FR167653, a selective inhibitor of TNF alpha and IL 1beta, while those in the Control group received vehicle only. Liver chemistry and serum levels of TNF alpha and IL-6 were measured serially. Liver specimens were obtained 48 hr after surgery and regenerative activity assessed by proliferating cell nuclear antigen (PCNA) expression and remnant liver weight.


RESULTS
The survival rate was significantly better in the FR group (76.4+/-11.7 hrs) than in the Control group (26.8+/-4.3 hrs, p=0.0014). Liver enzyme and blood sugar levels after surgery were higher in the FR group compared to the Control group (p=0.03 or less). Changes in serum levels of both TNF alpha and IL-6 were suppressed in FR group rats after surgery. Microscopically, hepatocellular damage and steatosis was less prominent in FR group livers. PCNA labeling index and residual liver weights were higher in the FR group (p<0.001).


CONCLUSIONS
Following extensive hepatectomy in rats, suppression of early cytokine induction improved liver function and facilitated liver regeneration. Suppression of selective cytokine responses could allow extended liver resection and reduced risk of liver failure.
Tsutsumi
Ryuji
R
Department of Transplantation and Digestive Surgery, Graduate School of Biomedical Science, Nagasaki University, Nagasaki, Japan.
Kamohara
Yukio
Y
Eguchi
Susumu
S
Azuma
Takashi
T
Fujioka
Hikaru
H
Okudaira
Sadayuki
S
Yanaga
Katsuhiko
K
Kanematsu
Takashi
T
D000818:Animals; D002455:Cell Division; D006498:Hepatectomy / Q000379:methods; D022781:Hepatocytes / Q000502:physiology; D007375:Interleukin-1 / Q000037:antagonists & inhibitors*; D008115:Liver Regeneration; D008297:Male; D011720:Pyrazoles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
C104334:FR 167653; D007375:Interleukin-1; D011720:Pyrazoles; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha