Attenuation of liver and lung injury after hepatic ischemia and reperfusion by a cytokine-suppressive agent, FR167653.
BACKGROUND
Hepatic ischemia/reperfusion (I/R) injury is an important clinical problem and leads to the release of the proinflammatory cytokines, TNF-alpha and IL-1. These cytokines play important roles in the induction of polymorphonuclear neutrophil (PMN) activation and infiltration, and induce not only localized hepatic injury but also remote organ injury, especially pulmonary injury. Using a total hepatic ischemia model in rats, we tested our hypothesis that suppression of TNF-alpha and IL-1 by FR167653 ameliorates I/R injury in the liver and lung.


METHODS
Male Wistar rats, weighing 240-280 g, were divided into 3 groups, an FR group, a control group and a sham group. In the FR group, FR167653 (1 mg/kg/h) was administered continuously to the animals for 30 min prior to the onset of ischemia and for 2 h after reperfusion. The control group received normal saline. A porto-systemic shunt was placed between the cecal branch of the portal vein and the jugular vein, and total hepatic ischemia was produced for 90 min. The sham group was treated with placement of the porto-systemic shunt only. The 1-week survival rate, liver enzyme activity, hepatic tissue blood flow (HTBF), cytokine mRNA expression, myeloperoxidase (MPO) activity and histological results were studied.


RESULTS
The 1-week survival rate and HTBF were significantly higher in the FR group than in the control group. Serum AST, ALT, and LDH levels were significantly lower in the FR group at 30 min, 1 h and 3 h after reperfusion. MPO levels in liver and lung tissue were also significantly lower in the FR group. The expression of IL-1beta mRNA remarkably decreased up to 6 h after reperfusion in the FR group.


CONCLUSIONS
We concluded that the inflammatory cytokines, IL-1beta, play important roles in hepatic I/R injury. FR167653 might ameliorate I/R injury and be useful in liver surgery with ischemia.
Hato
S
S
Department of Surgery II, Okayama University Medical School, Okayama, Japan. shatou@ncc.go.jp
Urakami
A
A
Yamano
T
T
Uemura
T
T
Ota
T
T
Hirai
R
R
Shimizu
N
N
D000818:Animals; D015152:Blotting, Northern; D016207:Cytokines / Q000037:antagonists & inhibitors*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007375:Interleukin-1 / Q000235:genetics; D007511:Ischemia / Q000401:mortality / Q000473:pathology*; D008099:Liver / Q000201:enzymology / Q000473:pathology*; D008102:Liver Circulation; D008168:Lung / Q000473:pathology*; D008297:Male; D009195:Peroxidase / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000037:antagonists & inhibitors; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000378:metabolism / Q000401:mortality / Q000473:pathology*
D016207:Cytokines; C104334:FR 167653; D007166:Immunosuppressive Agents; D007375:Interleukin-1; D011720:Pyrazoles; D011725:Pyridines; D012333:RNA, Messenger; D009195:Peroxidase