Liu P, McGuire G M, Fisher M A, Farhood A, Smith C W, Jaeschke H
Drug Metabolism Research, Upjohn Company, Kalamazoo, Michigan 49001.
Shock. 1995 Jan;3(1):56-62.
The potential role of reactive oxygen species generated by Kupffer cells and neutrophils was investigated in a model of endotoxin-enhanced liver injury after hepatic ischemia. Male Fischer rats were subjected to 20 min ischemia and reperfusion of up to 24 h; .5 mg/kg Salmonella enteritidis endotoxin was injected at 30 min of reperfusion. The animals developed severe liver injury resulting in 50% hepatocellular necrosis at 24 h. Isolated Kupffer cells and neutrophils from the postischemic liver generated 10-fold more superoxide than cells from control livers. Treatment with gadolinium chloride (GdCl3) selectively reduced the capacity of Kupffer cells to generate superoxide by 65% and attenuated liver injury by 73% at 4 h and 58-69% at 24 h. Monoclonal antibodies against neutrophil adhesion molecules (CD11/CD18) had no effect on the early injury but reduced hepatocellular necrosis by 90-95% at 24 h. The antioxidant Trolox and the iron-chelator deferoxamine attenuated liver injury by 71 and 80%, respectively. It is concluded that Kupffer cells are mainly responsible for the initial injury, and neutrophils are the dominant cytotoxic cell type during the later phase. Reactive oxygen generated by both cell types is critical for this pathogenesis.
在肝缺血后内毒素增强肝损伤的模型中，研究了库普弗细胞和中性粒细胞产生的活性氧的潜在作用。雄性Fischer大鼠经历20分钟的缺血和长达24小时的再灌注；在再灌注30分钟时注射0.5mg/kg肠炎沙门氏菌内毒素。动物出现严重肝损伤，在24小时时导致50%的肝细胞坏死。从缺血后肝脏分离的库普弗细胞和中性粒细胞产生的超氧化物比对照肝脏细胞多10倍。用氯化钆（GdCl3）处理可选择性地使库普弗细胞产生超氧化物的能力降低65%，并在4小时时使肝损伤减轻73%，在24小时时减轻58 - 69%。抗中性粒细胞粘附分子（CD11/CD18）的单克隆抗体对早期损伤无影响，但在24小时时使肝细胞坏死减少90 - 95%。抗氧化剂Trolox和铁螯合剂去铁胺分别使肝损伤减轻71%和80%。结论是，库普弗细胞主要负责初始损伤，而中性粒细胞是后期主要的细胞毒性细胞类型。两种细胞类型产生的活性氧对这种发病机制至关重要。
