Gabexate mesilate, a synthetic protease inhibitor, reduces ischemia/reperfusion injury of rat liver by inhibiting leukocyte activation

Objective: To investigate whether gabexate mesilate, a synthetic protease i nhibitor with anticoagulant properties, prevents hepatic damage by inhibiti ng leukocyte activation, we examined its effect on ischemia/reperfusion inj ury of rat liver in which activated leukocytes play a critical role. Design: Prospective, randomized, controlled study. Setting: Research laboratory at a university medical center. Subjects: Male Wistar rats weighing 220 to 280 g. Interventions: Hepatic damage was evaluated by changes in bile flow and ser um transaminase concentrations after ischemia/reperfusion. Rats received co ntinuous intravenous infusions of gabexate mesilate (10 mg/kg/hr) or intrav enous administration of an inactive derivative of activated factor X (Xa), a selective inhibitor of thrombin generation (3 mg/kg), immediately before the induction of ischemia in the median and left lobes of the liver. To det ermine whether gabexate mesilate inhibits leukocyte activation, we examined the effects of gabexate mesilate on hepatic concentrations of tumor necros is factor-alpha and rat interleukin-8 and on hepatic myeloperoxidase activi ty after ischemia/reperfusion. Measurements and Main Results: Hepatic dysfunction, observed after 60 mins of ischemia/reperfusion, showed a reduction in bile flow, The ischemia/repe rfusion-induced decrease in bile flow was prevented by administration of ga bexate mesilate. Serum transaminase concentrations increased after hepatic ischemia/reperfusion, peaking 12 hrs after reperfusion. Gabexate mesilate s ignificantly inhibited the ischemia/reperfusion-induced increase in serum t ransaminase levels seen 12 hrs after reperfusion. Although an inactive deri vative of factor Xa inhibited the increases in serum levels of fibrin and f ibrinogen degradation products 6 hrs after reperfusion, it did not prevent ischemia/reperfusion-induced liver injury, Hepatic levels of tumor necrosis factor-alpha, rat interleukin-8, and myeloperoxidase were significantly in creased after ischemia/reperfusion. These increases were significantly inhi bited by gabexate mesilate but unaffected by an inactive derivative of fact or Xa. Conclusion: Gaberate mesilate reduced ischemia/reperfusion induced hepatic injury not by inhibiting coagulation, but by inhibiting leukocyte activatio n.