Angiopoietin-2 is increased in severe sepsis: correlation with inflammatory mediators

• Published in: Critical care medicine Vol. 35; no. 1; p. 199
• Main Authors: Orfanos, Stylianos E, Kotanidou, Anastasia, Glynos, Constantinos, Athanasiou, Chariclea, Tsigkos, Stelios, Dimopoulou, Ioanna, Sotiropoulou, Christina, Zakynthinos, Spyros, Armaganidis, Apostolos, Papapetropoulos, Andreas, Roussos, Charis
• Format: Journal Article
• Language: English
• Published: United States 01.01.2007
• Subjects: Aged; Analysis of Variance; Angiopoietin-2 - blood; Angiopoietin-2 - immunology; APACHE; Case-Control Studies; Critical Illness; Endothelium, Vascular - cytology; Endothelium, Vascular - immunology; Female; Hospitals, University; Humans; Inflammation; Inflammation Mediators - blood; Inflammation Mediators - immunology; Interleukin-6 - blood; Interleukin-6 - immunology; Linear Models; Lung - blood supply; Male; Middle Aged; Prospective Studies; Regression Analysis; Sepsis - blood; Sepsis - classification; Sepsis - immunology; Severity of Illness Index; Systemic Inflammatory Response Syndrome - blood; Systemic Inflammatory Response Syndrome - classification; Systemic Inflammatory Response Syndrome - immunology; Tumor Necrosis Factor-alpha - blood; Tumor Necrosis Factor-alpha - immunology
• ISSN: 0090-3493; 1530-0293
• DOI: 10.1097/01.CCM.0000251640.77679.D7

Angiopoietin (Ang)-2 is an endothelium-specific growth factor, regulated by proinflammatory stimuli, that destabilizes vascular endothelium and increases vascular leakage; consequently, Ang-2 may contribute to sepsis pathophysiology. We have studied 1) serum Ang-2 levels in critically-ill patients and investigated potential relationships with inflammatory mediators and indices of disease severity and 2) the effect of sepsis-related inflammatory mediators on Ang-2 production by lung endothelium in vitro. Prospective clinical study followed by cell culture studies. General intensive care unit and research laboratory of a university hospital. Human and bovine lung microvascular endothelial cells and 61 patients (32 men). Patients were grouped according to their septic stage as having: no systemic inflammatory response syndrome (n = 6), systemic inflammatory response syndrome (n = 8), sepsis (n = 16), severe sepsis (n = 18), and septic shock (n = 13). Cells were exposed to lipopolysaccharide, tumor necrosis factor-alpha, and interleukin-6. Patients' serum Ang-2 levels were significantly increased in severe sepsis as compared with patients with no systemic inflammatory response syndrome or sepsis (p < .05 by analysis of variance). Positive linear relationships were observed with: serum tumor necrosis factor-alpha (rs = 0.654, p < .001), serum interleukin-6 (rs = 0.464, p < .001), Acute Physiology and Chronic Health Evaluation II score (rs = 0.387, p < .001), and Sequential Organ Failure Assessment score (rs = 0.428, p < .001). Multiple regression analysis revealed that serum Ang-2 is mostly related to serum tumor necrosis factor-alpha and severe sepsis. Treatment of human lung microvascular endothelial cells with all mediators resulted in a concentration-dependent Ang-2 reduction. Treatment of bovine lung microvascular endothelial cells with lipopolysaccharide and tumor necrosis factor-alpha increased Ang-2 release, and interleukin-6 reduced basal Ang-2 levels. First, patients' serum Ang-2 levels are increased during severe sepsis and associated with disease severity. The strong relationship of serum Ang-2 with serum tumor necrosis factor-alpha suggests that the latter may participate in the regulation of Ang-2 production in sepsis. Second, inflammatory mediators reduce Ang-2 release from human lung microvascular endothelial cells, implying that this vascular bed may not be the source of increased Ang-2 in human sepsis.