Ischemic preconditioning protects hepatocytes via reactive oxygen species derived from Kupffer cells in rats.
Ischemic preconditioning protects hepatocytes via reactive oxygen species derived from Kupffer cells in rats.
复制标题
DOI：
10.1053/j.gastro.2004.07.023
复制
发表时间：
2004-11
期刊：
影响因子：
29.4
通讯作者：
Kazuaki Tejima;M. Arai;H. Ikeda;T. Tomiya;M. Yanase;Y. Inoue;K. Nagashima;Takako Nishikawa;N. Watanabe;M. Omata;K. Fujiwara
中科院分区：
文献类型：
--
作者：
Kazuaki Tejima;M. Arai;H. Ikeda;T. Tomiya;M. Yanase;Y. Inoue;K. Nagashima;Takako Nishikawa;N. Watanabe;M. Omata;K. Fujiwara
背景与目的肝缺血预处理可减少大鼠冷缺血/再灌注后血管内皮细胞损伤和Kupffer细胞活化，从而提高肝移植受者的存活率。缺血预处理还可以保护肝脏免受热缺血/再灌注损伤，其中肝细胞损伤是显著的。我们的目的是确定缺血预处理是否直接保护肝细胞并阐明其机制。方法给大鼠注射氯化钆以消耗库普弗细胞，或用N -乙酰- 1 -半胱氨酸、超氧化物歧化酶或过氧化氢酶清除活性氧。然后对肝脏进行10分钟缺血和10分钟再灌注预处理。随后，肝脏在体内或肝脏灌注系统中进行40分钟的热缺血和60分钟的再灌注。在其他大鼠中，肝脏通过H(2)O(2)灌注而不是缺血进行预处理。在其他实验中，肝脏灌注硝基蓝四氮唑以检测活性氧的形成。结果缺血预处理可减轻肝细胞损伤，但对窦内皮细胞无明显影响。库普弗细胞耗竭本身不改变缺血再灌注后肝细胞的损伤，说明库普弗细胞对缺血再灌注损伤没有贡献。然而，Kupffer细胞耗竭逆转了缺血预处理的肝保护作用。缺血预处理后，Kupffer细胞发生活性氧形成。活性氧的清除逆转了缺血预处理的效果，而H(2)O(2)预处理模拟了缺血预处理。结论缺血预处理不像冷缺血再灌注损伤那样通过抑制肝窦细胞的变化而直接保护热缺血再灌注损伤后的肝细胞。这种肝细胞保护是由库普弗细胞产生的活性氧介导的。
BACKGROUND AND AIMS Hepatic ischemic preconditioning decreases sinusoidal endothelial cell injury and Kupffer cell activation after cold ischemia/reperfusion, leading to improved survival of liver transplant recipients in rats. Ischemic preconditioning also protects livers against warm ischemia/reperfusion injury, in which hepatocyte injury is remarkable. We aimed to determine whether ischemic preconditioning directly protects hepatocytes and to elucidate its mechanisms. METHODS Rats were injected with gadolinium chloride to deplete Kupffer cells or with N -acetyl- l -cysteine, superoxide dismutase, or catalase to scavenge reactive oxygen species. Livers were then preconditioned by 10 minutes of ischemia and 10 minutes of reperfusion. Subsequently, livers were subjected to 40 minutes of warm ischemia and 60 minutes of reperfusion in vivo or in a liver perfusion system. In other rats, livers were preconditioned by H(2)O(2) perfusion instead of ischemia. In the other experiments, livers were perfused with nitro blue tetrazolium to detect reactive oxygen species formation. RESULTS Ischemic preconditioning decreased injury in hepatocytes, but not in sinusoidal endothelial cells. Kupffer cell depletion itself did not change hepatocyte injury after ischemia/reperfusion, indicating no contribution of Kupffer cells to ischemia/reperfusion injury. However, Kupffer cell depletion reversed hepatoprotection by ischemic preconditioning. Reactive oxygen species formation occurred in Kupffer cells after ischemic preconditioning. Scavenging of reactive oxygen species reversed the effect of ischemic preconditioning, and H(2)O(2) preconditioning mimicked ischemic preconditioning. CONCLUSIONS Ischemic preconditioning directly protected hepatocytes after warm ischemia/reperfusion, which is not via suppression of changes in sinusoidal cells as in cold ischemia/reperfusion injury. This hepatocyte protection was mediated by reactive oxygen species produced by Kupffer cells.