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

Crit Care Med. 2012 Nov;40(11):3034-41. doi: 10.1097/CCM.0b013e31825fdc31.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 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


  • Angiopoietin-2