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

Abstract

OBJECTIVE In sepsis, quiescent blood vessels become leaky and inflamed by mechanisms that are incompletely understood. We hypothesized that Angiopoietin-2 (Angpt-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 Angpt-2 heterozygous mice, Emergency Department patients MEASUREMENTS AND MAIN RESULTS Mice with one functional Angpt-2 allele developed milder kidney and lung injury, less tissue inflammation, and less vascular leakage compared to wildtype counterparts. Heterozygotes experienced >40% absolute survival advantage following two different models of sepsis (p = 0.004 and 0.018). In human subjects presenting to our emergency department with suspected infection (n = 270 combined), circulating Angpt-2 was markedly elevated within the first hour of clinical care. First-hour Angpt-2 concentrations were proportional to current disease severity (p < 0.0001), rose further over time in eventual non-survivors (p < 0.0001), and predicted the future occurrence of shock (p < 0.0001) or death (p < 0.0001) 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 Angpt-2 monoclonal antibody. CONCLUSIONS We conclude that Angpt-2 induction precedes and contributes to the adverse outcomes in sepsis, opening a new avenue for therapeutic investigation.

Gene control of tyrosine kinase TIE2 and vascular manifestations of infections

“…Angpt-1 protects against vascular leakage and death in experimental sepsis (15,16). Similar protective effects arise with blockade, deletion, or depletion of Angpt-2 (1,4,6,30). However, the importance of Tie2 has been diminished by the identification of integrin receptors for Angpt-1 (11-13) and, more recently, for Angpt-2 (3,31).…”

“…enhances Tie2 activation and counteracts leakage (1,6,(15)(16)(17). The role of TIE2 gene expression has not been fully investigated in this and related settings.…”

“…First, Tie2 phosphorylation is tightly controlled by the interplay of several proteins: a paralogous receptor, Tie1; a tyrosine phosphatase, vascular endothelial-protein tyrosine phosphatase (VE-PTP); and two secreted ligands, angiopoietin (Angpt)-1 and Angpt-2, the latter of which can act as an agonist, partial agonist, or antagonist depending upon context (1)(2)(3)(4)(5)(6). Second, unlike classic growth factor receptors, Tie2 is heavily expressed and phosphorylated throughout the quiescent adult vasculature (7), suggesting that Tie2 signaling has one or more roles in vascular maintenance.…”

Therapeutic strategies in pneumonia: going beyond antibiotics

“…Furthermore, plasma Ang-2 levels had prognostic value for mortality in non-infection-related, but not in infection-related acute lung injury [84]. Besides being a marker of disease severity, a pathogenic role was ascribed to Ang-2 in sepsis as Ang-2 +/-mice with reduced Ang-2 levels were protected against lung injury [85]. In support of this conclusion, ZIEGLER et al [86] recently demonstrated that Ang-2 antibody treatment reduced permeability and mortality in mice upon LPS injection.…”

Are there new approaches for diagnosis, therapy guidance and outcome prediction of sepsis?

“…In a multicenter cohort study, low plasma levels of Ang-1 at admission as well as serially measured Ang-1 and -2 were associated with higher 28-d mortality in critically ill patients with severe sepsis [119] . Additionally, in patients with suspected infection, elevated Ang-2 plasma levels were detected during the first hour after admission and correlated with the development of severe sepsis and a higher mortality [120] . A number of trials investigate the value of an Ang-1/-2 ratio in predicting outcome of septic patients.…”