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.