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(The FASEB Journal. 1999;13:1239-1248.)
© 1999 FASEB

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

GUIDO A. WANNER*, LADISLAV MICA*, ELISABETH WANNER-SCHMID*, STEFAN A. KOLB{dagger}, HANNES HENTZE{ddagger}, OTMAR TRENTZ* and WOLFGANG ERTEL,*1

* Division of Trauma Surgery and
{dagger} Department of Pathology, University Hospital Zurich, CH-8091 Zurich, Switzerland; and
{ddagger} Department of Biochemical Pharmacology, University of Konstanz, D-78457 Konstanz, Germany

1Correspondence: Division of Trauma Surgery, University Hospital Zurich, Raemistr. 100, CH-8091 Zurich, Switzerland. E-mail: guido.wanner{at}chi.usz.ch

Using a murine model, we studied the effect of agonistic anti-CD95 antibodies (aCD95) on sinusoidal lining cells and a potential protection by caspase inhibition. C3H/HeN mice were intravenously administered aCD95 (10 µg/mouse) 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 failure and reduced (P<0.05) phagocytic activity of Kupffer cells (KC) within 2 h. Transmission electron micrographs demonstrated loss of integrity of sinusoidal endothelial cells as early as 1 h after aCD95 application, whereas histological manifestation of hepatocellular apoptosis and hemorrhagic necrosis was most pronounced at 6 h. Blocking of caspase activity attenuated (P<0.01) both hepatic microvascular perfusion failure and KC dysfunction. Accordingly, full protection of the liver from apoptotic damage and intact microarchitecture was observed in histological sections after z-VAD-fmk treatment. Mortality rate was 40% 6 h after aCD95 administration, whereas all animals survived in the z-VAD-fmk group (P<0.05). The activation of caspases through CD95 may primarily lead to damage of sinusoidal endothelial cells and hepatic microvascular perfusion failure. Moreover, reduced phagocytic capacity of KC may contribute to accumulation of toxic metabolites released by dying cells at the local site of inflammation, further aggravating liver injury.—Wanner, G. A., Mica, L., Wanner-Schmid, E., Kolb, S. A., Hentze, H., Trentz, O., Ertel, W. Inhibition of caspase activity prevents CD95-mediated hepatic microvascular perfusion failure and restores Kupffer cell clearance capacity.


Key Words: liver failure • apoptosis • hepatic microcirculation • cysteine protease




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