Angiopoietin-2 may contribute to multiple organ dysfunction and death in sepsis

: In sepsis, quiescent blood vessels become leaky and inflamed by mechanisms that are incompletely understood. We hypothesized that angiopoietin-2, a partial antagonist of the endothelium-stabilizing receptor Tie-2 secreted by endothelium, contributes to adverse outcomes in this disease. : Laborator...

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Bibliographic Details
Published in:Critical care medicine Vol. 40; no. 11; p. 3034
Main Authors: David, Sascha, Mukherjee, Aditi, Ghosh, Chandra C, Yano, Midori, Khankin, Eliyahu V, Wenger, Julia B, Karumanchi, S Ananth, Shapiro, Nathan I, Parikh, Samir M
Format: Journal Article
Language:English
Published: United States 01.11.2012
Subjects:
Adult
Aged
Aged, 80 and over
Angiopoietin-2 - genetics
Angiopoietin-2 - immunology
Angiopoietin-2 - physiology
Animals
Female
Heterozygote
Humans
Male
Mice
Mice, 129 Strain
Mice, Inbred C57BL
Middle Aged
Multiple Organ Failure - mortality
Multiple Organ Failure - physiopathology
Sepsis - mortality
Sepsis - physiopathology
Survival Analysis
ISSN:1530-0293, 1530-0293
Online Access:Get more information
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Summary:: In sepsis, quiescent blood vessels become leaky and inflamed by mechanisms that are incompletely understood. We hypothesized that angiopoietin-2, a partial antagonist of the endothelium-stabilizing receptor Tie-2 secreted by endothelium, contributes to adverse outcomes in this disease. : Laboratory and animal research. : Research laboratories and Emergency Department of Beth Israel Deaconess Medical Center, Boston, MA. : Angiopoietin-2 heterozygous mice, emergency department patients. : Mice with one functional angiopoietin-2 allele developed milder kidney and lung injury, less tissue inflammation, and less vascular leakage compared to wild-type counterparts. Heterozygotes experienced >40% absolute survival advantage following two different models of sepsis (p = .004 and .018). In human subjects presenting to our emergency department with suspected infection (n = 270 combined), circulating angiopoietin-2 was markedly elevated within the first hour of clinical care. First-hour angiopoietin-2 concentrations were proportional to current disease severity (p < .0001), rose further over time in eventual nonsurvivors (p < .0001), and predicted the future occurrence of shock (p < .0001) or death (p < .0001) in the original cohort and an independent validation group. Finally, septic human serum disrupted the barrier function of microvascular endothelial cells, an effect fully neutralized by an angiopoietin-2 monoclonal antibody. : We conclude that angiopoietin-2 induction precedes and contributes to the adverse outcomes in sepsis, opening a new avenue for therapeutic investigation.
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ISSN:1530-0293
1530-0293
DOI:10.1097/CCM.0b013e31825fdc31