title: Angiopoietin-2 is increased in severe sepsis: correlation with inflammatory mediators.
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.
  
  
  METHODS
  Prospective clinical study followed by cell culture studies.
  
  
  METHODS
  General intensive care unit and research laboratory of a university hospital.
  
  
  METHODS
  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).
  
  
  METHODS
  Cells were exposed to lipopolysaccharide, tumor necrosis factor-alpha, and interleukin-6.
  
  
  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-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.
  
  
  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-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.
authors.affiliation: Second Department of Critical Care, Attikon University Hospital, University of Athens Medical School, 1 Rimini Street, Haidari, Athens 124 62, Greece. sorfanos@med.uoa.gr
authors.forename: Stylianos E
authors.initials: SE
authors.lastname: Orfanos
authors.forename: Anastasia
authors.initials: A
authors.lastname: Kotanidou
authors.forename: Constantinos
authors.initials: C
authors.lastname: Glynos
authors.forename: Chariclea
authors.initials: C
authors.lastname: Athanasiou
authors.forename: Stelios
authors.initials: S
authors.lastname: Tsigkos
authors.forename: Ioanna
authors.initials: I
authors.lastname: Dimopoulou
authors.forename: Christina
authors.initials: C
authors.lastname: Sotiropoulou
authors.forename: Spyros
authors.initials: S
authors.lastname: Zakynthinos
authors.forename: Apostolos
authors.initials: A
authors.lastname: Armaganidis
authors.forename: Andreas
authors.initials: A
authors.lastname: Papapetropoulos
authors.forename: Charis
authors.initials: C
authors.lastname: Roussos
mesh_terms: D018806:APACHE; D000368:Aged; D000704:Analysis of Variance; D042702:Angiopoietin-2 / Q000097:blood / Q000276:immunology; D016022:Case-Control Studies; D016638:Critical Illness; D004730:Endothelium, Vascular / Q000166:cytology / Q000276:immunology; D005260:Female; D006785:Hospitals, University; D006801:Humans; D007249:Inflammation; D018836:Inflammation Mediators / Q000097:blood / Q000276:immunology; D015850:Interleukin-6 / Q000097:blood / Q000276:immunology; D016014:Linear Models; D008168:Lung / Q000098:blood supply; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D012044:Regression Analysis; D018805:Sepsis / Q000097:blood* / Q000145:classification / Q000276:immunology*; D012720:Severity of Illness Index; D018746:Systemic Inflammatory Response Syndrome / Q000097:blood* / Q000145:classification / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000276:immunology
chemical_list: D042702:Angiopoietin-2; D018836:Inflammation Mediators; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha