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 clini cal problem and leads to the release of the proinflammatory cytokines, TNF- alpha and IL-1. These cytokines play important roles in the induction of po lymorphonuclear neutrophil (PMN) activation and infiltration, and induce no t only localized hepatic injury but also remote organ injury, especially pu lmonary 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 240-2 80 g, were divided into 3 groups, an FR group, a control group and a sham g roup. In the FR group, FR167653 (1 mg/kg/h) was administered continuously t o the animals for 30 min prior to the onset of ischemia and for 2 h after r eperfusion. The control group received normal saline. A portosystemic shunt was placed between the cecal branch of the portal vein and the jugular vei n, and total hepatic ischemia was produced for 90 min. The sham group was t reated with placement of the porto-systemic shunt only. The 1-week survival rate, liver enzyme activity, hepatic tissue blood flow (HTBF), cytokine mR NA expression, myeloperoxidase (MPO) activity and histological results were studied. Results: The 1-week survival rate and HTBF were significantly hig her in the FR group than in the control group. Serum AST, ALT, and LDH leve ls were significantly lower in the FR group at 30 min, 1 h and 3 h after re perfusion. MPO levels in liver and lung tissue were also significantly lowe r in the FR group. The expression of IL-1 beta mRNA remarkably decreased up to 6 h after reperfusion in the FR group. Conclusions: We concluded that t he inflammatory cytokines, IL-1 beta, play important roles in hepatic I/R i njury. FR167653 might ameliorate I/R injury and be useful in liver surgery with ischemia. Copyright (C) 2001 S. Karger AG, Basel.