Anti-vascular endothelial growth factor antibody attenuates inflammation and decreases mortality in an experimental model of severe sepsis

Abstract

Despite decades of intense research, severe sepsis continues to be associated with an unacceptably high rate of mortality. Vascular endothelial growth factor (VEGF) is a potent angiogenic and vascular permeability factor. Recent studies revealed elevated VEGF levels in patients with sepsis, as well as an association between VEGF levels and sepsis severity. We report our investigation of the effect of anti-VEGF antibody (Bevacizumab, Bev) in an experimental model of sepsis. The experiments were performed using the murine cecal ligation and puncture (CLP) and endotoxemia models of sepsis, and human umbilical vein endothelial cells (HUVECs). The effect of Bev on mortality, vascular permeability, and expression of inflammatory cytokines was evaluated. Survival benefits in CLP and endotoxemia models were evident in mice given 0.1 mg/kg over the both control groups of differing doses of Bev (P < 0.001 and P = 0.028, respectively), and in 6 h post-treated mice over the CLP control group of differing time of Bev (P = 0.033). In addition, Bev-treatment inhibited LPS-induced vascular leak in the lung, spleen, and kidney in the murine endotoxemia model (P < 0.05). The expression of inflammatory cytokines on HUVECs after treatment of Bev and LPS revealed a significant decreased over the LPS-only treated HUVECs. Furthermore, levels of cytokines were significantly lower in Bev treated HUVECs. In conclusion, our investigation shows that anti-VEGF antibody may be a promising therapeutic agent due to its beneficial effects on the survival of sepsis by decreasing inflammatory responses and endothelial permeability.