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  • Title: Activated protein C protects vascular endothelial cells from apoptosis in malaria and in sepsis.
    Author: Hemmer CJ, Löbermann M, Unverricht M, Vogt A, Krause R, Reisinger EC.
    Journal: Trop Med Int Health; 2011 Aug; 16(8):906-13. PubMed ID: 21615630.
    Abstract:
    OBJECTIVE: In malaria and sepsis, apoptotic endothelial damage is preventable in vitro by antioxidants and protease inhibitors. Activated protein C, which has anti-apoptotic effects, improves survival in sepsis. Therefore, we studied whether activated protein C prevents endothelial cell apoptosis, induced by serum from patients with malaria or sepsis. METHODS: Endothelial cells were incubated with patient sera (Plasmodium falciparum malaria, Escherichia coli sepsis, Staphylococcus aureus sepsis) or culture supernatants of the respective organisms, with or without neutrophils. Activated protein C was used to reduce endothelial cell apoptosis in vitro. The proportion of apoptotic endothelial cells was determined by TUNEL staining. RESULTS: The apoptosis-inducing effect of patient sera or culture supernatants (P. falciparum, E. coli, S. aureus) on endothelial cells was augmented by neutrophils and reduced by activated protein C in the presence of neutrophils. Pre-incubating either endothelial cells or neutrophils with activated protein C also reduced the endothelial cell apoptosis rate. The pro-apoptotic effect of P. falciparum supernatant was reduced by pan-caspase inhibitor and caspase 8 inhibitor, but not by caspase 9 inhibitor. The pro-apoptotic effect of E. coli and S. aureus supernatants was also reduced by caspase 9 inhibitor. CONCLUSIONS: Activated protein C protects vascular endothelial cells from apoptosis triggered by patient sera or culture supernatants in combination with neutrophils. It seems to act both on neutrophils and on endothelial cells. Activated protein C blocks caspase-8-dependent apoptosis, which accounts for endothelial damage in sepsis and malaria. Therefore, activated protein C might offer clinical benefit not only in sepsis but also in malaria.
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