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


METHODS
: Laboratory and animal research.


METHODS
: Research laboratories and Emergency Department of Beth Israel Deaconess Medical Center, Boston, MA.


METHODS
: Angiopoietin-2 heterozygous mice, emergency department patients.


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.
Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
Sascha
S
David
Aditi
A
Mukherjee
Chandra C
CC
Ghosh
Midori
M
Yano
Eliyahu V
EV
Khankin
Julia B
JB
Wenger
S Ananth
SA
Karumanchi
Nathan I
NI
Shapiro
Samir M
SM
Parikh
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D042702:Angiopoietin-2 / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D000818:Animals; D005260:Female; D006579:Heterozygote; D006801:Humans; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009102:Multiple Organ Failure / Q000401:mortality / Q000503:physiopathology*; D018805:Sepsis / Q000401:mortality / Q000503:physiopathology*; D016019:Survival Analysis
D042702:Angiopoietin-2