Abstract
IntroductionSevere sepsis is associated with an unacceptably high rate of mortality. Recent studies revealed elevated levels of vascular endothelial growth factor (VEGF), a potent angiogenic and vascular permeability factor, in patients with sepsis. There was also an association between VEGF levels and sepsis severity. Here we investigate the effects of an anti-VEGF antibody (Bevacizumab, Bev) in an experimental model of sepsis.MethodsHuman umbilical vein endothelial cells (HUVECs), murine cecal ligation and puncture (CLP), and endotoxemia models of sepsis were used. HUVECs were treated with lipopolysaccharide (LPS) and/or Bev, harvested and cytokine mRNA levels determined using a semi-quantitative reverse transcription-polymerase chain reaction assay. The levels of inflammatory cytokine were also determined in HUVECs supernatants. In addition, the effects of Bev on mortality in the CLP and endotoxemia models of sepsis were evaluated.ResultsTreatment with Bev and LPS significantly decreased the expression and the level of inflammatory cytokines in HUVECs relative to LPS alone. In CLP and endotoxemia models, survival benefits were evident in mice given 0.1 mg/kg of Bev relative to the CLP or LPS alone (P <0.001 and P = 0.028, respectively), and in 6 h post-treated mice relative to the CLP alone for the effect of different 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).ConclusionsAnti-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.
Highlights
Severe sepsis is associated with an unacceptably high rate of mortality
In cecal ligation and puncture (CLP) and endotoxemia models, survival benefits were evident in mice given 0.1 mg/kg of Bev relative to the CLP or LPS alone (P
monocyte chemotactic protein-1 (MCP-1) and RANTES levels were significantly decreased when LPS was administered with 50 μg/ml Bev compared to the LPS-only group
Summary
Recent studies revealed elevated levels of vascular endothelial growth factor (VEGF), a potent angiogenic and vascular permeability factor, in patients with sepsis. A disconnect exists between hyper-acute experimental animal models and human sepsis illustrated by the failure of several clinical trials of Vascular endothelial growth factor (VEGF) was first identified and characterized as a vascular permeability factor and subsequently reported to promote proliferation, migration and survival of endothelial cells [4,5,6]. VEGF induces the expression of cellular adhesion molecules including E-selectin, intercellular adhesion molecule 1 (ICAM-1), and vascular cell adhesion molecule 1 (VCAM-1) in endothelial cells and promotes the adhesion of leukocytes [8,9]. Two independent studies reported an association between human sepsis/septic shock and elevated circulating levels of VEGF [11,12]
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