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Critical Care

, 17:R97

First Online: 27 May 2013Received: 12 November 2012Revised: 05 February 2013Accepted: 27 May 2013

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.

Keywordssepsis vascular endothelial growth factor bevacizumab anti-VEGF antibody AbbreviationsBevbevacizumab

CCK-8cell counting kit-8

CLPcecal ligation and puncture

CX3CL1C-X3-C motif ligand 1

FBSfetal bovine serum

HUVECshuman umbilical vein endothelial cells

ICAM-1intercellular adhesion molecule 1

IL-βinterleukin-1β

IL-6interleukin-6

i.p.intraperitoneal

LPSlipopolysaccharide

MCP-1monocyte chemotactic protein-1

ODoptical density

PBSphosphate-buffered solution

PIGFplacental growth factor

RANTESregulated on activation: normal T-cell expressed and secreted

rhAPCrecombinant activated protein C

TLRtoll-like receptor

TNF-αtumor necrosis factor-α

VCAM-1vascular cell adhesion molecule 1

VEGFvascular endothelial growth factor

VEGFRvascular endothelial growth factor receptor

Electronic supplementary materialThe online version of this article doi:10.1186-cc12742 contains supplementary material, which is available to authorized users.

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Autor: Su Jin Jeong - Sang Hoon Han - Chang Oh Kim - Jun Yong Choi - June Myung Kim

Fuente: https://link.springer.com/







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