ACTIVATION OF KUPFFER CELLS AND NEUTROPHILS FOR REACTIVE OXYGEN FORMATION IS RESPONSIBLE FOR ENDOTOXIN-ENHANCED LIVER-INJURY AFTER HEPATIC ISCHEMIA

The potential role of reactive oxygen species generated by Kupffer cel ls and neutrophils was investigated in a model of endotoxin-enhanced l iver injury after hepatic ischemia. Male Fischer rats were subjected t o 20 min ischemia and reperfusion of up to 24 h; .5 mg/kg Salmonella e nteritidis endotoxin was injected at 30 min of reperfusion. The animal s developed severe liver injury resulting in 50% hepatocellular necros is at 24 h. Isolated Kupffer cells and neutrophils from the postischem ic liver generated 10-fold more superoxide than cells from control liv ers. Treatment with gadolinium chloride (GdCl3) selectively reduced th e capacity of Kupffer cells to generate superoxide by 65% and attenuat ed liver injury by 73% at 4 h and 58-69% at 24 h. Monoclonal antibodie s against neutrophil adhesion molecules (CD11/CD18) had no effect on t he 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.