Angiopoietin-2 is increased in severe sepsis: correlation with inflammatory mediators.
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.
Orfanos
Stylianos E
SE
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
Kotanidou
Anastasia
A
Glynos
Constantinos
C
Athanasiou
Chariclea
C
Tsigkos
Stelios
S
Dimopoulou
Ioanna
I
Sotiropoulou
Christina
C
Zakynthinos
Spyros
S
Armaganidis
Apostolos
A
Papapetropoulos
Andreas
A
Roussos
Charis
C
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
D042702:Angiopoietin-2; D018836:Inflammation Mediators; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha