1. Time course of angiopoietin-2 release during experimental human endotoxemia and sepsis
- Author
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Hermann Haller, Philipp Kümpers, Johan Bijzet, Alexander Lukasz, Jan G. Zijlstra, Frank Biertz, Matijs van Meurs, Grietje Molema, Sascha David, and Groningen Kidney Center (GKC)
- Subjects
Lipopolysaccharides ,Male ,Time Factors ,Critical Care and Intensive Care Medicine ,p38 Mitogen-Activated Protein Kinases ,biology ,ACTIVATED PROTEIN-KINASE ,EXCESS CIRCULATING ANGIOPOIETIN-2 ,Middle Aged ,Prognosis ,medicine.anatomical_structure ,ANIMAL-MODELS ,cardiovascular system ,Female ,Tumor necrosis factor alpha ,medicine.symptom ,E-Selectin ,CRITICALLY-ILL PATIENTS ,hormones, hormone substitutes, and hormone antagonists ,Adult ,EXPRESSION ,Endothelium ,Inflammation ,Sensitivity and Specificity ,Proinflammatory cytokine ,Angiopoietin-2 ,Sepsis ,Angiopoietin ,Endothelial activation ,ORGAN DYSFUNCTION ,INFLAMMATION ,E-selectin ,medicine ,TIE-2 LIGAND ANGIOPOIETIN-2 ,Humans ,Aged ,Tumor Necrosis Factor-alpha ,business.industry ,Research ,MORTALITY ,SEPTIC SHOCK ,medicine.disease ,Survival Analysis ,Endotoxemia ,Immunology ,biology.protein ,Endothelium, Vascular ,business ,Cell Adhesion Molecules ,Biomarkers - Abstract
Introduction Endothelial activation leading to vascular barrier breakdown denotes a devastating event in sepsis. Angiopoietin (Ang)-2, a circulating antagonistic ligand of the endothelial specific Tie2 receptor, is rapidly released from Weibel-Palade and has been identified as a non-redundant gatekeeper of endothelial activation. We aimed to study: the time course of Ang-2 release during human experimental endotoxemia; the association of Ang-2 with soluble adhesion molecules and inflammatory cytokines; and the early time course of Ang-2 release during sepsis in critically ill patients.Methods In 22 healthy volunteers during a 24-hour period after a single intravenous injection of lipopolysaccharide (LPS; 4 ng/kg) the following measurement were taken by immuno luminometric assay (ILMA), ELISA, and bead-based multiplex technology: circulating Ang-1, Ang-2, soluble Tie2 receptor, the inflammatory molecules TNF-alpha, IL-6, IL-8 and C-reactive protein, and the soluble endothelial adhesion molecules intercellular adhesion molecule-1 (ICAM-1), E-selectin, and P-selectin. A single oral dose of placebo or the p38 mitogen activated protein (MAP) kinase inhibitor drug, RWJ-67657, was administered 30 minutes before the endotoxin infusion. In addition, the course of circulating Ang-2 was analyzed in 21 septic patients at intensive care unit (ICU) admission and after 24 and 72 hours, respectively.Results During endotoxemia, circulating Ang-2 levels were significantly elevated, reaching peak levels 4.5 hours after LPS infusion. Ang-2 exhibited a kinetic profile similar to early proinflammatory cytokines TNF-alpha, IL-6, and IL-8. Ang-2 levels peaked prior to soluble endothelial-specific adhesion molecules. Finally, Ang-2 correlated with TNF-alpha levels (r = 0.61, P = 0.003), soluble E-selectin levels (r = 0.64, P Conclusions LPS is a triggering factor for Ang-2 release in men. Circulating Ang-2 appears in the systemic circulation during experimental human endotoxemia in a distinctive temporal sequence and correlates with TNF-alpha and E-selectin levels. In addition, not only higher baseline Ang-2 concentrations, but also a persistent increase in Ang-2 during the early course identifies septic patients with unfavorable outcome.
- Published
- 2009