Time course of angiopoietin-2 release during experimental human endotoxemia and sepsis.
BACKGROUND
Endothelial activation leading to vascular barrier breakdown denotes a devastating event in sepsis. Angiopoietin (Ang)-2, a circulating antagonistic ligand of the endothelial specific Tie2 receptor, is rapidly released from Weibel-Palade and has been identified as a non-redundant gatekeeper of endothelial activation. We aimed to study: the time course of Ang-2 release during human experimental endotoxemia; the association of Ang-2 with soluble adhesion molecules and inflammatory cytokines; and the early time course of Ang-2 release during sepsis in critically ill patients.


METHODS
In 22 healthy volunteers during a 24-hour period after a single intravenous injection of lipopolysaccharide (LPS; 4 ng/kg) the following measurement were taken by immuno luminometric assay (ILMA), ELISA, and bead-based multiplex technology: circulating Ang-1, Ang-2, soluble Tie2 receptor, the inflammatory molecules TNF-alpha, IL-6, IL-8 and C-reactive protein, and the soluble endothelial adhesion molecules inter-cellular adhesion molecule-1 (ICAM-1), E-selectin, and P-selectin. A single oral dose of placebo or the p38 mitogen activated protein (MAP) kinase inhibitor drug, RWJ-67657, was administered 30 minutes before the endotoxin infusion. In addition, the course of circulating Ang-2 was analyzed in 21 septic patients at intensive care unit (ICU) admission and after 24 and 72 hours, respectively.


RESULTS
During endotoxemia, circulating Ang-2 levels were significantly elevated, reaching peak levels 4.5 hours after LPS infusion. Ang-2 exhibited a kinetic profile similar to early pro-inflammatory cytokines TNF-alpha, IL-6, and IL-8. Ang-2 levels peaked prior to soluble endothelial-specific adhesion molecules. Finally, Ang-2 correlated with TNF-alpha levels (r = 0.61, P = 0.003), soluble E-selectin levels (r = 0.64, P < 0.002), and the heart rate/mean arterial pressure index (r = 0.75, P < 0.0001). In septic patients, Ang-2 increased in non-survivors only, and was significantly higher compared with survivors at baseline, 24 hours, and 72 hours.


CONCLUSIONS
LPS is a triggering factor for Ang-2 release in men. Circulating Ang-2 appears in the systemic circulation during experimental human endotoxemia in a distinctive temporal sequence and correlates with TNF-alpha and E-selectin levels. In addition, not only higher baseline Ang-2 concentrations, but also a persistent increase in Ang-2 during the early course identifies septic patients with unfavorable outcome.
Kümpers
Philipp
P
Department of Nephrology & Hypertension, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany. kuempers.philipp@mh-hannover.de
van Meurs
Matijs
M
David
Sascha
S
Molema
Grietje
G
Bijzet
Johan
J
Lukasz
Alexander
A
Biertz
Frank
F
Haller
Hermann
H
Zijlstra
Jan G
JG
D000328:Adult; D000368:Aged; D042702:Angiopoietin-2 / Q000097:blood*; D015415:Biomarkers / Q000097:blood; D015815:Cell Adhesion Molecules / Q000097:blood; D019040:E-Selectin / Q000097:blood; D004730:Endothelium, Vascular / Q000378:metabolism; D019446:Endotoxemia / Q000097:blood* / Q000175:diagnosis; D005260:Female; D006801:Humans; D008070:Lipopolysaccharides; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D012680:Sensitivity and Specificity; D018805:Sepsis / Q000097:blood* / Q000175:diagnosis; D016019:Survival Analysis; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors
D042702:Angiopoietin-2; D015415:Biomarkers; D015815:Cell Adhesion Molecules; D019040:E-Selectin; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases