Beneficial effects of inducible nitric oxide synthase inhibitor on reperfusion injury in the pig liver
Beneficial effects of inducible nitric oxide synthase inhibitor on reperfusion injury in the pig liver
复制标题
DOI：
10.1097/00007890-199909270-00013
复制
发表时间：
1999-09-27
期刊：
影响因子：
6.2
通讯作者：
Matsuno, T
中科院分区：
文献类型：
--
作者：
Isobe, M;Katsuramaki, T;Matsuno, T
背景：虽然内皮型一氧化氮合酶（eNOS）的抑制可加重肝缺血再灌注（I/R）损伤，但诱导型一氧化氮合酶（iNOS）的作用尚不清楚，我们研究了iNOS产生NO的作用，并评价了iNOS抑制剂对猪肝脏长时间温性YR损伤的影响。猪在体外循环下进行120 min的肝脏热I/R。我们采用免疫组织化学方法，包括双免疫荧光技术联合激光共聚焦扫描显微镜，研究了血清和肝脏微透析液NO2- + NO3- (NOx)变化的时间过程以及eNOS和iNOS的细胞分布。研究了iNOS抑制剂的作用。肝脏VR诱导再灌注后血清和肝脏微透析液NOx产生新的一氧化氮，并在小叶中心区强烈表达硝基酪氨酸，造成严重的肝损伤。再灌注前后血管内皮弥漫性eNOS表达无明显差异。再灌注后，小叶中心区Kupffer细胞和中性粒细胞强烈表达iNOS。经门静脉注射n - g -硝基- l -精氨酸（10 mg/kg）可使猪在缺血期或再灌注期早期死亡，死亡率高达80.0%。门内注射半硫酸氨基胍（10 mg/kg）可显著抑制再灌注后一氧化氮生成和血清天冬氨酸转氨酶，抑制硝基酪氨酸表达，减轻肝损伤。这些结果表明，肝脏VR损伤是由小叶中心iNOS表达引发的；并通过抑制iNOS而减弱。
Background, Although inhibition of endothelial nitric oxide synthase (eNOS) has been reported to aggravate hepatic ischemia-reperfusion (I/R) injury, the role of inducible nitric oxide synthase (iNOS) has been still unknown, We investigated the role of NO produced by iNOS, and evaluated the effect of an iNOS inhibitor on prolonged warm YR injury in the pig liver.Methods. Pigs were subjected to 120 min of hepatic warm I/R under the extracorporeal circulation. We investigated the time course of changes in serum and hepatic microdialysate NO2- + NO3- (NOx) and the cellular distribution of eNOS and iNOS by immunohistochemistry, including a double-immunofluorescence technique in combination with confocal laser scanning microscopy. The effect of iNOS inhibitor was also investigated.Results. Hepatic VR induced new nitric oxide production in serum and hepatic microdialysate NOx after reperfusion and severe hepatic damage in the centrilobular region where nitrotyrosine was strongly expressed. Diffuse eNOS expression in sinusoidal endothelium did not differ before and after reperfusion. In contrast, strong iNOS expression in Kupffer cells and neutrophils appeared strongly in the centrilobular region after reperfusion. Pigs with intraportal administration of N-G-nitro-L-arginine (10 mg/kg) died during the period of ischemia or early in the period of reperfusion with a high mortality rate (80.0%). Intraportal administration of aminoguanidine hemisulfate (10 mg/kg) significantly suppressed nitric oxide production and serum aspartate aminotransferase after reperfusion, inhibited nitrotyrosine expression, and attenuated hepatic damage.Conclusions. These results indicate that hepatic VR injury is triggered by centrilobular iNOS expression; and attenuated by inhibition of iNOS.