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

Stylianos E. Orfanos, Anastasia Kotanidou, Constantinos Glynos, Chariclea Athanasiou, Stelios Tsigkos, Ioanna Dimopoulou, Christina Sotiropoulou, Spyros Zakynthinos, Apostolos Armaganidis, Andreas Papapetropoulos, Charis Roussos

Research output: Contribution to journalArticle

155 Citations (Scopus)

Abstract

OBJECTIVE: 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. DESIGN: Prospective clinical study followed by cell culture studies. SETTING: General intensive care unit and research laboratory of a university hospital. SUBJECTS: 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). INTERVENTIONS: Cells were exposed to lipopolysaccharide, tumor necrosis factor-α, and interleukin-6. MEASUREMENTS AND MAIN RESULTS: 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-α (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-α 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-α increased Ang-2 release, and interleukin-6 reduced basal Ang-2 levels. CONCLUSIONS: 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-α 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.

Original languageEnglish (US)
Pages (from-to)199-206
Number of pages8
JournalCritical Care Medicine
Volume35
Issue number1
DOIs
StatePublished - Jan 1 2007
Externally publishedYes

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Angiopoietin-2
Sepsis
Serum
Tumor Necrosis Factor-alpha
Systemic Inflammatory Response Syndrome
Lung
Endothelial Cells
Interleukin-6
Endothelium
Lipopolysaccharides
Organ Dysfunction Scores
APACHE
Vascular Endothelium
Septic Shock
Critical Illness
Blood Vessels
Intensive Care Units

Keywords

  • Angiopoietin-2
  • Endothelium
  • Interleukin-6
  • Lung
  • Sepsis
  • Tumor necrosis factor-α

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine

Cite this

Orfanos, S. E., Kotanidou, A., Glynos, C., Athanasiou, C., Tsigkos, S., Dimopoulou, I., ... Roussos, C. (2007). Angiopoietin-2 is increased in severe sepsis: Correlation with inflammatory mediators. Critical Care Medicine, 35(1), 199-206. https://doi.org/10.1097/01.CCM.0000251640.77679.D7

Angiopoietin-2 is increased in severe sepsis : Correlation with inflammatory mediators. / Orfanos, Stylianos E.; Kotanidou, Anastasia; Glynos, Constantinos; Athanasiou, Chariclea; Tsigkos, Stelios; Dimopoulou, Ioanna; Sotiropoulou, Christina; Zakynthinos, Spyros; Armaganidis, Apostolos; Papapetropoulos, Andreas; Roussos, Charis.

In: Critical Care Medicine, Vol. 35, No. 1, 01.01.2007, p. 199-206.

Research output: Contribution to journalArticle

Orfanos, SE, Kotanidou, A, Glynos, C, Athanasiou, C, Tsigkos, S, Dimopoulou, I, Sotiropoulou, C, Zakynthinos, S, Armaganidis, A, Papapetropoulos, A & Roussos, C 2007, 'Angiopoietin-2 is increased in severe sepsis: Correlation with inflammatory mediators', Critical Care Medicine, vol. 35, no. 1, pp. 199-206. https://doi.org/10.1097/01.CCM.0000251640.77679.D7
Orfanos SE, Kotanidou A, Glynos C, Athanasiou C, Tsigkos S, Dimopoulou I et al. Angiopoietin-2 is increased in severe sepsis: Correlation with inflammatory mediators. Critical Care Medicine. 2007 Jan 1;35(1):199-206. https://doi.org/10.1097/01.CCM.0000251640.77679.D7
Orfanos, Stylianos E. ; Kotanidou, Anastasia ; Glynos, Constantinos ; Athanasiou, Chariclea ; Tsigkos, Stelios ; Dimopoulou, Ioanna ; Sotiropoulou, Christina ; Zakynthinos, Spyros ; Armaganidis, Apostolos ; Papapetropoulos, Andreas ; Roussos, Charis. / Angiopoietin-2 is increased in severe sepsis : Correlation with inflammatory mediators. In: Critical Care Medicine. 2007 ; Vol. 35, No. 1. pp. 199-206.
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T2 - Correlation with inflammatory mediators

AU - Orfanos, Stylianos E.

AU - Kotanidou, Anastasia

AU - Glynos, Constantinos

AU - Athanasiou, Chariclea

AU - Tsigkos, Stelios

AU - Dimopoulou, Ioanna

AU - Sotiropoulou, Christina

AU - Zakynthinos, Spyros

AU - Armaganidis, Apostolos

AU - Papapetropoulos, Andreas

AU - Roussos, Charis

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N2 - OBJECTIVE: 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. DESIGN: Prospective clinical study followed by cell culture studies. SETTING: General intensive care unit and research laboratory of a university hospital. SUBJECTS: 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). INTERVENTIONS: Cells were exposed to lipopolysaccharide, tumor necrosis factor-α, and interleukin-6. MEASUREMENTS AND MAIN RESULTS: 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-α (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-α 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-α increased Ang-2 release, and interleukin-6 reduced basal Ang-2 levels. CONCLUSIONS: 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-α 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.

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KW - Endothelium

KW - Interleukin-6

KW - Lung

KW - Sepsis

KW - Tumor necrosis factor-α

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