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 hepa tic vasculature in various models of liver injury including galactosamine/e ndotoxin (Gal/ET) shock and the anti-Fas antibody (Ab)-mediated liver failu re model in C3Heb/FeJ mice. However, the mechanism of injury to the sinusoi dal lining cells is unknown. Because apoptosis occurs in both models, it wa s investigated whether apoptosis in nonparenchymal cells could be the mecha nism 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 p arenchymal cell necrosis. Thus, parenchymal and nonparen-chymal cells were isolated 6 h after Gal/ET and 45 min after anti-Fas Ab administration. In b oth models there was a significant increase of caspase-3 activity and DNA-f ragmentation in paren-chymal cells indicating apoptotic cell injury. In con trast, 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 microcirculator y disturbances are caused by nonparenchymal cell apoptosis. In contrast, tr ansmigrated and cytotoxically active neutrophils appear to be responsible f or the damage to the sinusoidal lining cells in the Gal/ET model.