Attenuation of liver and lung injury after hepatic ischemia and reperfusion by a cytokine-suppressive agent, FR167653
Attenuation of liver and lung injury after hepatic ischemia and reperfusion by a cytokine-suppressive agent, FR167653
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DOI：
10.1159/000049707
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发表时间：
2001-05-01
影响因子：
1.6
通讯作者：
Shimizu, N
中科院分区：
文献类型：
--
作者：
Hato, S;Urakami, A;Shimizu, N
背景肝脏缺血/再灌注（I/R）损伤是一个重要的临床问题，并导致促炎细胞因子TNF-α和IL-1的释放。这些细胞因子在诱导中性粒细胞（PMN）活化和浸润中起重要作用，不仅可引起局限性肝损伤，而且可引起远隔器官损伤，尤其是肺损伤。使用大鼠全肝缺血模型，我们测试了我们的假设，即FR 167653抑制TNF-α和IL-1可改善肝和肺的I/R损伤。方法：雄性Wistar大鼠，体重240-280 g，随机分为3组：FR组、对照组和假手术组。在FR组中，在缺血发作前30分钟和再灌注后2小时连续向动物施用FR 167653（1 mg/kg/h）。对照组给予生理盐水。门体分流之间的门静脉和颈静脉的盲肠分支，并产生总肝缺血90分钟。假手术组只与门体分流的位置进行治疗。观察1周存活率、肝酶活性、肝组织血流量（HTBF）、细胞因子mRNA表达、髓过氧化物酶（MPO）活性及肝组织学变化。结果：FR组1周生存率和HTBF均显著高于对照组。再灌注后30 min、1 h和3 h，FR组血清AST、ALT和LDH水平显著降低。FR组肝、肺组织中MPO水平也显著降低。FR组IL-1 β mRNA表达在再灌注后6 h明显下降。结论：IL-1 β在肝I/R损伤中起重要作用。FR 167653可能改善I/R损伤，在缺血性肝脏手术中有一定的应用价值。版权所有（C）2001 S. Karger AG，巴塞尔。
Background. Hepatic ischemia/reperfusion (I/R) injury is an important clinical problem and leads to the release of the proinflammatory cytokines, TNF-alpha and IL-1. These cytokines play important roles in the induction of polymorphonuclear neutrophil (PMN) activation and infiltration, and induce not only localized hepatic injury but also remote organ injury, especially pulmonary injury. Using a total hepatic ischemia model in rats, we tested our hypothesis that suppression of TNF-alpha and IL-1 by FR167653 ameliorates I/R injury in the liver and lung. Methods: Male Wistar rats, weighing 240-280 g, were divided into 3 groups, an FR group, a control group and a sham group. In the FR group, FR167653 (1 mg/kg/h) was administered continuously to the animals for 30 min prior to the onset of ischemia and for 2 h after reperfusion. The control group received normal saline. A portosystemic shunt was placed between the cecal branch of the portal vein and the jugular vein, and total hepatic ischemia was produced for 90 min. The sham group was treated with placement of the porto-systemic shunt only. The 1-week survival rate, liver enzyme activity, hepatic tissue blood flow (HTBF), cytokine mRNA expression, myeloperoxidase (MPO) activity and histological results were studied. Results: The 1-week survival rate and HTBF were significantly higher in the FR group than in the control group. Serum AST, ALT, and LDH levels were significantly lower in the FR group at 30 min, 1 h and 3 h after reperfusion. MPO levels in liver and lung tissue were also significantly lower in the FR group. The expression of IL-1 beta mRNA remarkably decreased up to 6 h after reperfusion in the FR group. Conclusions: We concluded that the inflammatory cytokines, IL-1 beta, play important roles in hepatic I/R injury. FR167653 might ameliorate I/R injury and be useful in liver surgery with ischemia. Copyright (C) 2001 S. Karger AG, Basel.