ATTENUATION OF ISCHEMIC LIVER-INJURY BY MONOCLONAL ANTI-ENDOTHELIN ANTIBODY, AWETN40

Background: Enhanced production of endothelin-l (ET-1), vasoconstricti ve 21 amino acids produced by endothelial cells during ischemia and af ter reperfusion of the liver, is known to cause sinusoidal constrictio n and microcirculatory disturbances, which lead to severe tissue damag e. Using a 2-hour hepatic vascular exclusion model in dogs, we tested our hypothesis that neutralization of ET-I by monoclonal anti-ET-l and anti-ET-2 antibody (AwETN40) abates vascular dysfunction and ameliora tes ischemia/reperfusion injury of the liver. Study Design: After skel etonization, the liver was made totally ischemic by cross-clamping the portal vein, the hepatic artery, and the vena cava (above and below t he liver). Veno-venous bypass was used to decompress splanchnic and in ferior systemic congestion. AwETN40, 5 mg/kg, was administered intrave nously 10 minutes before ischemia (treatment group, n = 5). Nontreated animals were used as controls (control group, n = 10). Animal surviva l, hepatic tissue blood flow, liver function tests, total bile acid, h igh-energy phosphate, ET-1 levels, and liver histopathology were studi ed. Results: Treatment with AwETN40 improved 2-week animal survival fr om 30% to 100%. Hepatic tissue blood flow after reperfusion was signif icantly higher in the treatment group. The treatment significantly att enuated liver enzyme release, total bile acid, and changes in adenine nucleotides. Immunoreactive ET-1 levels in the hepatic venous blood of the control group showed a significant increase and remained high for up to 24 hours after reperfusion. Histopathologic alterations were si gnificantly lessened in the treatment group. Conclusions: These result s indicate that ET-1 is involved in ischemia/reperfusion injury of the liver, which can be ameliorated by the monoclonal anti-ET-l and anti- ET-2 antibody AwETN40. (C) 1997 by the American College of Surgeons.