Malaria and bacterial sepsis: similar mechanisms of endothelial apoptosis and its prevention in vitro.

OBJECTIVE AND DESIGN

Apoptotic endothelial damage contributes to multiorgan failure in Plasmodium falciparum malaria and in sepsis. In malaria, endothelial apoptosis is amplified by neutrophils and their secretory products, and reduced by inhibitors of neutrophil-derived substances in vitro. We compared the mechanisms of endothelial apoptosis in malaria and in sepsis, using the human umbilical vein endothelial cell as a model.

INTERVENTIONS

Endothelial cells were incubated with patient sera (P. falciparum malaria, Escherichia coli sepsis, Staphylococcus aureus sepsis) or culture supernatants of the respective organisms, with or without neutrophils. Ascorbic acid or ulinastatin was used to neutralize reactive oxygen species or elastase secreted by neutrophils. Transwell sieve inserts or antibodies against leukocyte function antigen 1 or intercellular adhesion molecule 1 was used to study the effect of direct interaction between neutrophils and endothelial cells. The rate of apoptotic endothelial cells was determined by TUNEL and annexin staining.

MEASUREMENTS AND MAIN RESULTS

Incubation of endothelial cells with patient sera or culture supernatants (P. falciparum, E. coli, S. aureus) lead to higher apoptosis rates, compared with incubation with control sera or control supernatants. Addition of neutrophils augmented the apoptosis rate further. Addition of ascorbic acid or ulinastatin reduced endothelial apoptosis in the presence of neutrophils. Separation of neutrophils from endothelial cells with Transwell sieve inserts, or addition of anti-leukocyte function antigen-1 antibodies also reduced endothelial cell apoptosis. However, addition of anti-intercellular adhesion molecule-1 antibodies restored high apoptosis rates that had been reduced by Transwell inserts.

CONCLUSIONS

These in vitro results show how neutrophils can contribute to endothelial damage in malaria and in sepsis, both by their secretory products and by binding to intercellular adhesion molecule-1 on endothelial cells. The presence of similar pathomechanisms suggests that similar antiapoptotic strategies may offer potential benefit in malaria and in sepsis.