Apoptosis versus neutrophil-mediated injury of sinusoidal lining cells during endotoxin shock and anti-Fas antibody-mediated injury

Injury to sinusoidal lining cells is responsible for hemorrhage in the hepatic vasculature in various models of liver injury including galactosamine/endotoxin (Gal/ET) shock and the anti-Fas antibody (Ab)-mediated liver failure model in C3Heb/FeJ mice. However, the mechanism of injury to the sinusoidal lining cells is unknown. Because apoptosis occurs in both models, it was investigated whether apoptosis in nonparenchymal cells could be the mechanism of cell injury. Hemorrhage (indicated by increase in tissue hemoglobin levels) occurred between 6-7 h after Gal/ET and 1-2 h after anti-Fits Ab, i.e. parallel to the increase in plasma ALT activities and development of parenchymal cell necrosis. Thus, parenchymal and nonparen-chymal cells were isolated 6 h after Gal/ET and 45 min after anti-Fas Ab administration. In both models there was a significant increase of caspase-3 activity and DNA-fragmentation in paren-chymal cells indicating apoptotic cell injury. In contrast, caspase-3 activity and DNA-fragmentation were significantly elevated in the nonparenchymal cell fraction only after anti-Fas Ab treatment. Thus, in the anti-Fas Ab model, severe hemorrhage and potential microcirculatory disturbances are caused by nonparenchymal cell apoptosis. In contrast, transmigrated and cytotoxically active neutrophils appear to be responsible for the damage to the sinusoidal lining cells in the Gal/ET model.