Glutathione peroxidase-deficient mice are more susceptible to neutrophil-mediated hepatic parenchymal cell injury during endotoxemia: Importance of an intracellular oxidant stress
Glutathione peroxidase-deficient mice are more susceptible to neutrophil-mediated hepatic parenchymal cell injury during endotoxemia: Importance of an intracellular oxidant stress
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DOI：
10.1002/hep.510290222
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发表时间：
1999-02-01
期刊：
影响因子：
13.5
通讯作者：
Farhood, A
中科院分区：
文献类型：
--
作者：
Jaeschke, H;Ho, YS;Farhood, A
中性粒细胞在许多急性炎症反应中对肝细胞造成损伤。然而，实质细胞损伤的分子机制仍存在争议。为了探讨活性氧(ROS)是否在肝损伤过程中起重要作用，我们采用了氨基半乳糖/内毒素(Gal/ET)急性肝衰竭模型，该模型涉及中性粒细胞介导的实质细胞损伤。在C3Heb/FEJ小鼠中，Gal/ET在中性粒细胞介导的损伤阶段选择性地诱导肝脏和血浆中氧化应激指标谷胱甘肽二硫化物(GSSG)的水平显著升高，而Gal/ET或Gal/肿瘤坏死因子α(TNF-α)与野生型动物相比导致更严重的中性粒细胞介导的肝损伤。然而，其他关键参数，如转录因子、核因子-kappaB(NF-kappa B)和可溶性细胞间黏附分子-1(sICAM-1)的激活，实质细胞的凋亡和中性粒细胞在肝脏中的隔离没有显著差异，我们的结果表明，中性粒细胞衍生的ROS参与了Gal/ET治疗后肝细胞内的氧化应激。由于GPX1-/-小鼠对中性粒细胞介导的损伤具有较高的敏感性，我们得出结论，中性粒细胞产生的过氧化物质扩散到肝细胞中，导致体内实质细胞的死亡。因此，加强靶细胞对ROS的防御机制可以在不影响宿主防御反应的情况下减轻过度的炎性损伤。
Neutrophils contribute to hepatocellular injury in a number of acute inflammatory reactions. However, the molecular mechanism of parenchymal cell injury remains controversial. To address the issue of whether or not reactive oxygen species (ROS) are important in the injury process, we used the galactosamine/endotoxin (Gal/ET) model of acute liver failure, which involves a neutrophil-mediated parenchymal cell injury. In C3Heb/FeJ mice, Gal/ET induced a significant increase of hepatic and plasma levels of glutathione disulfide (GSSG), an indicator of oxidant stress, selectively during the neutrophil-mediated injury phase, In glutathione peroxidase-deficient mice (Gpx1(-/-)), Gal/ET or Gal/tumor necrosis factor alpha (TNF-alpha) caused more severe neutrophil-mediated liver injury compared with wild-type animals. However, there was no significant difference in other critical parameters, e.g., activation Of the transcription factor, nuclear factor-kappa B (NF-kappa B), and soluble intercellular adhesion molecule-1 (sICAM-1), parenchymal cell apoptosis, and neutrophil sequestration in the liver, Our results suggest that neutrophil-derived ROS are responsible for an intracellular oxidant stress in hepatocytes after Gal/ET treatment. Because of the higher susceptibility of Gpx1-/- mice to a neutrophil-mediated injury, we conclude that peroxides generated by neutrophils diffused into hepatocytes and contributed to parenchymal cell death in vivo. Thus, strengthening defense mechanisms against ROS in target cells can attenuate excessive inflammatory injury without affecting host defense reactions.