Inhibition of caspase activity prevents CD95-mediated hepatic microvascular perfusion failure and restores Kupffer cell clearance capacity

Using a murine model, we studied the effect of agonistic anti-CD95 antibodi es (aCD95) on sinusoidal lining cells and a potential protection by caspase inhibition. C3H/HeN mice were intravenously administered aCD95 (10 mu g/mo use) or unspecific IgG (control) in the presence or absence of the caspase inhibitor z-VAD-fmk, Analysis of hepatic microcirculation using intravital fluorescence microscopy revealed severe (P<0.01) sinusoidal perfusion failu re and reduced (P<0.05) phagocytic activity of Kupffer cells (KC) within 2 h. Transmission electron micrographs demonstrated loss of integrity of sinu soidal endothelial cells as early as 1 h after aCD95 application, whereas h istological manifestation of hepatocellular apoptosis and hemorrhagic necro sis was most pronounced at 6 h, Blocking of caspase activity attenuated (P< 0.01) both hepatic microvascular perfusion failure and KC dysfunction, Acco rdingly, full protection of the liver from apoptotic damage and intact micr oarchitecture was observed in histological sections after z-VAD-fmk treatme nt. Mortality rate was 40% 6 h after aCD95 administration, whereas all anim als survived in the z-VAD-fmk group (P<0.05), The activation of caspases th rough CD95 may primarily lead to damage of sinusoidal endothelial cells and hepatic microvascular perfusion failure. Moreover, reduced phagocytic capa city of KC may contribute to accumulation of toxic metabolites released by dying cells at the local site of inflammation, further aggravating liver in jury.