A. Urakami et al., ATTENUATION OF ISCHEMIC LIVER-INJURY BY MONOCLONAL ANTI-ENDOTHELIN ANTIBODY, AWETN40, Journal of the American College of Surgeons, 185(4), 1997, pp. 358-364
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.