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

Sascha David, Aditi Mukherjee, Chandra C. Ghosh, Midori Yano, Eliyahu V. Khankin, Julia B. Wenger, S. Ananth Karumanchi, Nathan I. Shapiro, Samir M. Parikh

Research output: Contribution to journalArticlepeer-review

114 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3034-3041
Number of pages8
JournalCritical care medicine
Volume40
Issue number11
DOIs
StatePublished - Nov 2012
Externally publishedYes

Keywords

  • angiopoietin-2
  • endothelium
  • multiple organ dysfunction
  • sepsis
  • tie-2
  • vasculature

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine

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