TY - JOUR
T1 - Angiopoietin-2 may contribute to multiple organ dysfunction and death in sepsis
AU - David, Sascha
AU - Mukherjee, Aditi
AU - Ghosh, Chandra C.
AU - Yano, Midori
AU - Khankin, Eliyahu V.
AU - Wenger, Julia B.
AU - Ananth Karumanchi, S.
AU - Shapiro, Nathan I.
AU - Parikh, Samir M.
PY - 2012/11
Y1 - 2012/11
N2 - Objective: 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. Design: Laboratory and animal research. Settings: Research laboratories and Emergency Department of Beth Israel Deaconess Medical Center, Boston, MA. Subjects: Angiopoietin-2 heterozygous mice, emergency department patients. Measurements and Main Results: 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. Conclusions: We conclude that angiopoietin-2 induction precedes and contributes to the adverse outcomes in sepsis, opening a new avenue for therapeutic investigation.
AB - Objective: 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. Design: Laboratory and animal research. Settings: Research laboratories and Emergency Department of Beth Israel Deaconess Medical Center, Boston, MA. Subjects: Angiopoietin-2 heterozygous mice, emergency department patients. Measurements and Main Results: 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. Conclusions: We conclude that angiopoietin-2 induction precedes and contributes to the adverse outcomes in sepsis, opening a new avenue for therapeutic investigation.
KW - angiopoietin-2
KW - endothelium
KW - multiple organ dysfunction
KW - sepsis
KW - tie-2
KW - vasculature
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U2 - 10.1097/CCM.0b013e31825fdc31
DO - 10.1097/CCM.0b013e31825fdc31
M3 - Article
C2 - 22890252
AN - SCOPUS:84868196659
SN - 0090-3493
VL - 40
SP - 3034
EP - 3041
JO - Critical care medicine
JF - Critical care medicine
IS - 11
ER -