Soejima Y, Yanaga K, Nishizaki T, Yoshizumi T, Uchiyama H, Sugimachi K
Faculty of Medicine, Kyushu University, Fukuoka, 812-8582, Japan.
J Surg Res. 1999 Sep;86(1):150-4. doi: 10.1006/jsre.1999.5661.
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 the 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 lactated Ringer's solution and transplanted orthotopically. Recipients were divided into three groups: Vehicle group, 5-h preservation and vehicle (n = 8); ONO-5046 group, 5-h preservation and administration of ONO-5046 (n = 8); and Control group, minimum preservation only (n = 8). Bile output after reperfusion was significantly larger in the ONO-5046 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. Liver tissue energy charge 120 min after reperfusion was significantly better in the ONO-5046 group compared to the Vehicle group (P < 0.05). Furthermore, the number of neutrophils infiltrating the allograft after reperfusion was significantly depressed in the ONO-5046 group compared to the Vehicle group (P < 0. 02). These data suggest that the neutrophil elastase might cause liver damage early after reperfusion in cold-stored liver, which can be ameliorated by the administration of a specific neutrophil elastase inhibitor, ONO-5046.
活化的中性粒细胞通过释放氧自由基和弹性蛋白酶等毒性介质，被认为在肝脏缺血/再灌注损伤中起重要作用。在本研究中，我们评估了一种新型特异性中性粒细胞弹性蛋白酶抑制剂（ONO-5046）对啮齿动物肝脏同种异体移植冷缺血/再灌注损伤的影响。取雄性Lewis大鼠的肝脏，置于乳酸林格氏液中4℃冷藏保存后原位移植。受体分为三组：溶剂组，5小时保存并给予溶剂（n = 8）；ONO-5046组，5小时保存并给予ONO-5046（n = 8）；对照组，仅进行最短时间保存（n = 8）。再灌注后，ONO-5046组的胆汁分泌量显著高于溶剂组（P < 0.05或更低）。以再灌注120分钟时血清透明质酸浓度表示的窦状内皮细胞功能，ONO-5046组显著低于溶剂组（17.0±7.9对36.2±14.9 ng/ml，P < 0.05），而两组再灌注120分钟后的血清转氨酶水平相当。再灌注120分钟后，ONO-5046组的肝组织能量电荷明显优于溶剂组（P < 0.05）。此外，与溶剂组相比，ONO-5046组再灌注后浸润同种异体移植物的中性粒细胞数量显著减少（P < 0.02）。这些数据表明，中性粒细胞弹性蛋白酶可能在冷保存肝脏再灌注后早期导致肝损伤，而给予特异性中性粒细胞弹性蛋白酶抑制剂ONO-5046可改善这种损伤。
