Mechanisms of ischemic injury are different in the steatotic and normal rat liver
Mechanisms of ischemic injury are different in the steatotic and normal rat liver
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DOI：
10.1053/jhep.2000.20528
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发表时间：
2000-12-01
期刊：
影响因子：
13.5
通讯作者：
Clavien, PA
中科院分区：
文献类型：
--
作者：
Selzner, M;Rüdiger, HA;Clavien, PA
肝脏脂肪变性与肝切除和移植后的显著发病率和死亡率有关。尽管细胞凋亡是正常肝脏再灌注损伤的关键机制，但导致脂肪变性肝细胞死亡的途径尚不清楚。采用肥胖和瘦Zucker大鼠肝脏缺血再灌注损伤模型。与瘦动物相比，肥胖动物在缺血60分钟后天冬氨酸氨基转移酶(AST)的释放增加，存活率降低。细胞凋亡是瘦鼠的主要死亡形式(82%)，而坏死很少。相比之下，肥胖动物只出现中等程度的细胞凋亡，但在再灌注24小时后出现大量坏死(73%)。脂肪变性大鼠肝细胞内caspase8、caspase3和细胞色素c的表达明显低于瘦肝小鼠，提示肝细胞凋亡途径激活功能障碍。脂肪变性大鼠的高坏死率与脂肪大鼠再灌流24小时后的肾脏急性肾小管坏死有关，而瘦小的大鼠则没有。抑制半胱氨酸天冬氨酸氨基转移酶可显著减少瘦肉动物的再灌注损伤，但对肥胖动物无效。结果表明，脂肪肝对再灌注损伤的易感性增加与从细胞死亡的凋亡型转变为坏死型有关。我们得出结论，新的治疗策略对脂肪肝是必要的。
Hepatic steatosis is associated with significant morbidity and mortality after liver resection and transplantation. Although apoptosis is a key mechanism of reperfusion injury in the normal liver, the pathway leading to cell death in steatotic hepatocytes is unknown. A model of hepatic ischemia and reperfusion injury in fatty and lean Zucker rats was used. Fatty animals had increased aspartate aminotransferase (AST) release and decreased survival after 60 minutes of ischemia compared with lean animals. Apoptosis was the predominant form of cell death in the lean rats (82%), whereas necrosis was minimal. In contrast, fatty animals developed only moderate amounts of apoptosis but showed massive necrosis (73%) after 24 hours of reperfusion. Intracellular mediators of apoptosis, such as caspase 8, caspase 3, and cytochrome c, were significantly lower in the steatotic than in the lean liver indicating dysfunction in activation of the apoptotic pathway. The high percentage of necrosis in the steatotic rats was associated with renal acute tubular necrosis after 24 hours of reperfusion in the fatty, but not in lean rats. Caspase inhibition significantly decreased reperfusion injury in lean animals, but was ineffective in fatty animals. The results indicate that the increased susceptibility of fatty livers to reperfusion injury is associated with a change from an apoptotic form of cell death to necrosis. We conclude that new therapeutic strategies are necessary in the fatty liver.