Soluble vascular endothelial growth factor receptor-1 protects mice in sepsis.

OBJECTIVE

To determine the putative role in the modulation of inflammation of a soluble form of Flt-1 (sFlt), a potent vascular endothelial growth factor antagonist, in experimental endotoxemia and sepsis.

DESIGN

Randomized prospective experimental study.

SETTING

University medical laboratory.

SUBJECTS

Male C56BL/6 strain mice.

INTERVENTIONS

We investigated the expression patterns and the effects of vascular endothelial growth factor and soluble Flt-1 in experimental endotoxic shock and sepsis. The possible anti-inflammatory mechanism of soluble Flt-1 was also evaluated.

MEASUREMENTS AND MAIN RESULTS

Both vascular endothelial growth factor and sFlt-1 were rapidly released from macrophages activated in vitro by lipopolysaccharide and in the plasma of endotoxemic mice. Administration of vascular endothelial growth factor enhanced proinflammatory cytokine production and mediated a dramatic increase in mortality in endotoxemic mice. Treatment with sFlt-1 attenuated inflammatory responses, inhibited recruitment of inflammatory cells into the peritoneal cavity, and improved survival in a lethal endotoxemia and cecal ligation and puncture-induced sepsis model, even when administered as late as 24 hrs after the onset of sepsis.

CONCLUSIONS

These findings support a critical protective role of sFlt-1 in endotoxic shock and sepsis. sFlt-1 may therefore have utility as an adjunctive agent for the treatment of sepsis syndrome.