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

Harada, Naoaki MD; Okajima, Kenji MD; Kushimoto, Shigeki MD

Laboratory Investigations
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Objective: To investigate whether gabexate mesilate, a synthetic protease inhibitor with anticoagulant properties, prevents hepatic damage by inhibiting leukocyte activation, we examined its effect on ischemia/reperfusion injury 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 serum transaminase concentrations after ischemia/reperfusion. Rats received continuous intravenous infusions of gabexate mesilate (10 mg/kg/hr) or intravenous 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 determine whether gabexate mesilate inhibits leukocyte activation, we examined the effects of gabexate mesilate on hepatic concentrations of tumor necrosis factor-α and rat interleukin-8 and on hepatic myeloperoxidase activity after ischemia/reperfusion.

Measurements and Main Results: Hepatic dysfunction, observed after 60 mins of ischemia/reperfusion, showed a reduction in bile flow. The ischemia/reperfusion-induced decrease in bile flow was prevented by administration of gabexate mesilate. Serum transaminase concentrations increased after hepatic ischemia/reperfusion, peaking 12 hrs after reperfusion. Gabexate mesilate significantly inhibited the ischemia/reperfusion-induced increase in serum transaminase levels seen 12 hrs after reperfusion. Although an inactive derivative of factor Xa inhibited the increases in serum levels of fibrin and fibrinogen degradation products 6 hrs after reperfusion, it did not prevent ischemia/reperfusion-induced liver injury. Hepatic levels of tumor necrosis factor-α, rat interleukin-8, and myeloperoxidase were significantly increased after ischemia/reperfusion. These increases were significantly inhibited by gabexate mesilate but unaffected by an inactive derivative of factor Xa.

Conclusion: Gabexate mesilate reduced ischemia/reperfusion-induced hepatic injury not by inhibiting coagulation, but by inhibiting leukocyte activation.

From the Department of Laboratory Medicine, Kumamoto University School of Medicine, Kumamoto, Japan.

Supported, in part, by departmental funds of the Kumamoto University School of Medicine.

Address requests for reprints to: Kenji Okajima, MD, Department of Laboratory Medicine, Kumamoto University School of Medicine, Honjo 1-1-1, Kumamoto 860-8556, Japan. E-mail: whynot@kaiju.medic.kumamoto-u.ac.jp.

© 1999 Lippincott Williams & Wilkins, Inc.