Abstract
IntroductionThe endothelial specific angiopoietin (Ang)-Tie2 ligand-receptor system has been identified as a non-redundant mediator of endothelial activation in experimental sepsis. Binding of circulating Ang-1 to the Tie2 receptor protects the vasculature from inflammation and leakage, whereas binding of Ang-2 antagonises Tie2 signalling and disrupts endothelial barrier function. Here, we examine whether circulating Ang-1 and/or Ang-2 independently predict mortality in a cohort of critically ill medical patients.MethodsCirculating vascular endothelial growth factor (VEGF), Ang-1 and Ang-2 were prospectively measured in sera from 29 healthy controls and 43 medical ICU patients by immunoradiometric assay (IRMA) and ELISA, respectively. Survival after 30 days was the primary outcome studied.ResultsMedian serum Ang-2 concentrations were increasingly higher across the following groups: healthy controls, patients without sepsis, patients with sepsis and patients with septic shock. In contrast, Ang-1 and VEGF concentrations were significantly lower in all patient groups compared with healthy controls. Ang-2 correlated with partial pressure of oxygen in arterial blood (PaO2)/fraction of inspired oxygen (FiO2), tissue hypoxia, Sequential Organ Failure Assessment (SOFA) and Physiology and Chronic Health Evaluation II (APACHE II) score. Multivariate Cox regression analyses confirmed a strong independent prognostic impact of high Ang-2 as a novel marker of 30-day survival.ConclusionsA marked imbalance of the Ang-Tie system in favour of Ang-2 is present in critically ill medical patients. Our findings highlight the independent prognostic impact of circulating Ang-2 in critical illness. Ang-2 may be used as a readily available powerful predictor of outcome and may open new perspectives to individualise treatment in the ICU.
Highlights
The endothelial specific angiopoietin (Ang)-Tie2 ligand-receptor system has been identified as a non-redundant mediator of endothelial activation in experimental sepsis
A marked imbalance of the Ang-Tie system in favour of Ang-2 is present in critically ill medical patients
Understood as an important regulator in vessel maturation and remodelling, recent studies demonstrated that the Ang-Tie2 system regulates angiogenesis, and controls endothelial inflammation in a nonredundant manner [7,8,9]
Summary
The endothelial specific angiopoietin (Ang)-Tie ligand-receptor system has been identified as a non-redundant mediator of endothelial activation in experimental sepsis. In response to numerous different stimuli, 'quiescent' endothelial cells (anti-coagulant, anti-adhesive) undergo dramatic phenotypic changes towards an 'activated', pro-coagulant, pro-adhesive state, which is paralleled by disassembly of adherence junctions (e.g. VE-cadherin) and myosin driven cell contraction, resulting in interendothelial gap formation [1,2]. This highly regulated cascade of events results in net extravasation of fluid, a profound decrease in systemic vascular tone, collapse of the microcirculation and subsequent distributive shock, acute respiratory distress syndrome (ARDS) and eventually multiple organ dysfunction syndrome (MODS) [1,3,4,5]. Understood as an important regulator in vessel maturation and remodelling, recent studies demonstrated that the Ang-Tie system regulates angiogenesis, and controls endothelial inflammation in a nonredundant manner [7,8,9]
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