title: Vascular endothelial growth factor blockade reduces plasma cytokines in a murine model of polymicrobial sepsis.
abstract: Numerous cytokines, including vascular endothelial growth factor (VEGF), are implicated in the pathogenesis of sepsis. While overexpression of VEGF produces pulmonary capillary leak, the role of VEGF in sepsis is less clear. We investigated VEGF in sepsis, utilizing a VEGF trap (VEGF(T)). Polymicrobial sepsis was induced in C57BL/6 mice by cecal ligation and puncture (CLP) and resulted in significantly increased plasma VEGF levels (234 vs. 46 pg/mL; p = 0.03). Inhibition of VEGF had no effect on mortality or lung leak but did attenuate plasma IL-6 (120 vs. 236 ng/mL; p = 0.02) and IL-10 (16 vs. 41 ng/mL; p = 0.03). These alterations in inflammatory cytokines were associated with increased levels of the dominant negative inhibitory C/EBPbeta. In vitro, VEGF stimulated IL-6, IL-10 and reduced the inhibitory isoform of C/EBPbeta in cultured macrophages. Together these data suggest VEGF can regulate inflammatory cytokine production in murine polymicrobial sepsis, via regulation of C/EBPbeta.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, New York University School of Medicine, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Nolan
authors.forename: Michael D
authors.initials: MD
authors.lastname: Weiden
authors.forename: Gavin
authors.initials: G
authors.lastname: Thurston
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Gold
mesh_terms: D000818:Animals; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000032:analysis / Q000378:metabolism; D002199:Capillary Permeability; D002432:Cecum / Q000601:surgery; D002460:Cell Line; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D016753:Interleukin-10 / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D008026:Ligation; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000098:blood supply / Q000473:pathology*; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D017978:Receptors, Growth Factor / Q000008:administration & dosage; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage; D018805:Sepsis / Q000097:blood / Q000209:etiology / Q000473:pathology*; D016019:Survival Analysis; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000097:blood / Q000494:pharmacology
chemical_list: D022782:CCAAT-Enhancer-Binding Protein-beta; D015850:Interleukin-6; D017978:Receptors, Growth Factor; D011993:Recombinant Fusion Proteins; C460365:VEGF Trap R1R2 protein; D042461:Vascular Endothelial Growth Factor A; D016753:Interleukin-10