Effect of specific neutrophil elastase inhibitor on ischemia/reperfusion injury in rat liver transplantation

Activated neutrophils have been implicated as playing an important role in ischemia/reperfusion injury of the liver by releasing toxic mediators such as oxygen free radicals and elastases. In the present study, we evaluated t he effect of a novel, specific neutrophil elastase inhibitor (ONO-5046) on cold-ischemia/reperfusion injury of the liver allograft in rodents. Livers from male Lewis rats were procured and stored cold (4 degrees C) in lactate d Ringer's solution and transplanted orthotopically. Recipients were divide d into three groups: Vehicle group, 5-h preservation and vehicle (n = 8); O NO-5046 group, 5-h preservation and administration of ONO-5046 (n = 8); and Control group, minimum preservation only (n = 8). Bile output after reperf usion was significantly larger in the ONO5046 group compared to the Vehicle group (P < 0.05 or less). Sinusoidal endothelial cell function represented by the serum hyaluronic acid concentration at 120 min after reperfusion of the ONO-5046 group was significantly lower than that in the Vehicle group (17.0 +/- 7.9 vs 36.2 +/- 14.9 ng/ml, P < 0.05), whereas serum transaminase levels 120 min after reperfusion were comparable between the two groups. L iver tissue energy charge 120 min after reperfusion was significantly bette r in the ONO-5046 group compared to the Vehicle group (P < 0.05). Furthermo re, the number of neutrophils infiltrating the allograft after reperfusion was significantly depressed in the ONO-5046 group compared to the Vehicle g roup (P < 0.02). These data suggest that the neutrophil elastase might caus e liver damage early after reperfusion in cold stored liver, which can be a meliorated by the administration of a specific neutrophil elastase inhibito r, ONO5046. (C) 1999 Academic Press.