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Published on: August 7, 2012
Inhibition of caspase activity prevents CD95-mediated hepatic microvascular perfusion failure and restores Kupffer
G A Wanner1, L Mica, E Wanner-Schmid
1Division of Trauma Surgery and Department of Pathology, University Hospital Zurich, CH-8091 Zurich, Switzerland. guido.wanner@chi.usz.ch
Insights
Agonistic anti-CD95 antibodies cause liver injury by damaging sinusoidal cells and impairing Kupffer cells. Caspase inhibition protected mice from this damage and improved survival.
Area of Science:
- Hepatology
- Immunology
- Cell Biology
Background:
- CD95 activation triggers apoptosis.
- The role of CD95 in liver injury and microcirculation is not fully understood.
Purpose of the Study:
- To investigate the effects of agonistic anti-CD95 antibodies (aCD95) on liver sinusoidal cells.
- To evaluate the protective role of caspase inhibition against aCD95-induced liver injury.
Main Methods:
- Murine model (C3H/HeN mice) treated with aCD95 or IgG.
- Intravital fluorescence microscopy for hepatic microcirculation analysis.
- Transmission electron microscopy for cellular integrity assessment.
- Histological analysis for apoptosis and necrosis.
- Caspase inhibitor (z-VAD-fmk) used for protection studies.
Main Results:
- aCD95 caused severe sinusoidal perfusion failure and reduced Kupffer cell (KC) phagocytic activity.
- Loss of sinusoidal endothelial cell integrity occurred within 1 hour.
- Hepatocellular apoptosis and necrosis were pronounced at 6 hours.
- Caspase inhibition significantly attenuated microvascular perfusion failure and KC dysfunction.
- z-VAD-fmk treatment prevented liver damage and improved survival rates (0% vs 40% mortality).
Conclusions:
- CD95 activation primarily damages sinusoidal endothelial cells, leading to microvascular perfusion failure.
- Impaired KC phagocytosis contributes to liver injury by metabolite accumulation.
- Caspase inhibition offers significant protection against CD95-mediated liver damage.
Abstract:
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 microgram/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.
