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

• 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
• DOI: 10.1097/ccm.0b013e31825fdc31

: 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.