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Open Access 01-06-2009 | Research

Time course of angiopoietin-2 release during experimental human endotoxemia and sepsis

Authors: Philipp Kümpers, Matijs van Meurs, Sascha David, Grietje Molema, Johan Bijzet, Alexander Lukasz, Frank Biertz, Hermann Haller, Jan G Zijlstra

Published in: Critical Care | Issue 3/2009

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 inter-cellular 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 pro-inflammatory 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 < 0.002), and the heart rate/mean arterial pressure index (r = 0.75, P < 0.0001). In septic patients, Ang-2 increased in non-survivors only, and was significantly higher compared with survivors at baseline, 24 hours, and 72 hours.

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.

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Title: Time course of angiopoietin-2 release during experimental human endotoxemia and sepsis
Authors: Philipp Kümpers
Matijs van Meurs
Sascha David
Grietje Molema
Johan Bijzet
Alexander Lukasz
Frank Biertz
Hermann Haller
Jan G Zijlstra
Publication date: 01-06-2009
Publisher: BioMed Central
Published in: Critical Care / Issue 3/2009
Electronic ISSN: 1364-8535
DOI: https://doi.org/10.1186/cc7866

At a glance: The STEP trials

Springer Medicine

Time course of angiopoietin-2 release during experimental human endotoxemia and sepsis

Abstract

Introduction

Methods

Results

Conclusions

At a glance: The STEP trials

Springer Medicine

Abstract

Introduction

Methods

Results

Conclusions

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