Angiopoietin-2 Enhances Survival in Experimental Sepsis Induced by Multidrug-Resistant<i>Pseudomonas aeruginosa</i>

Tzepi, Ira-Maria; Giamarellos‐Bourboulis, Evangelos J.; Carrer, Dionyssia Pinelopi; Τσαγανός, Θωμάς; Claus, Ralf A.; Vaki, Ilia; Πελεκάνου, Αιμιλία; Kotsaki, Antigone; Tziortzioti, Vassiliki; Topouzis, Stavros; Bauer, Michael; Papapetropoulos, Andreas

doi:10.1124/jpet.112.195180

Cited by 20 publications

(22 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…However, ANG2 pretreatment did not provide a survival advantage after LPS treatment, rather revealing a trend toward lower survival (25). Moreover, in the study by Tzepi et al, pretreatment with 25 μg/kg human recombinant ANG2 was exogenously applied, differing from our strategy of inhibition of endogenous ANG2 activity upon LPS endotoxemia ( Figure 5I).…”

Section: Methodsmentioning

confidence: 90%

Angiopoietin 2 mediates microvascular and hemodynamic alterations in sepsis

et al. 2013

View full text Add to dashboard Cite

Septic shock is characterized by increased vascular permeability and hypotension despite increased cardiac output. Numerous vasoactive cytokines are upregulated during sepsis, including angiopoietin 2 (ANG2), which increases vascular permeability. Here we report that mice engineered to inducibly overexpress ANG2 in the endothelium developed sepsis-like hemodynamic alterations, including systemic hypotension, increased cardiac output, and dilatory cardiomyopathy. Conversely, mice with cardiomyocyte-restricted ANG2 overexpression failed to develop hemodynamic alterations. Interestingly, the hemodynamic alterations associated with endothelial-specific overexpression of ANG2 and the loss of capillary-associated pericytes were reversed by intravenous injections of adeno-associated viruses (AAVs) transducing cDNA for angiopoietin 1, a TIE2 ligand that antagonizes ANG2, or AAVs encoding PDGFB, a chemoattractant for pericytes. To confirm the role of ANG2 in sepsis, we i.p. injected LPS into C57BL/6J mice, which rapidly developed hypotension, acute pericyte loss, and increased vascular permeability. Importantly, ANG2 antibody treatment attenuated LPS-induced hemodynamic alterations and reduced the mortality rate at 36 hours from 95% to 61%. These data indicate that ANG2-mediated microvascular disintegration contributes to septic shock and that inhibition of the ANG2/ TIE2 interaction during sepsis is a potential therapeutic target.

show abstract

Section: Methodsmentioning

confidence: 90%

Angiopoietin 2 mediates microvascular and hemodynamic alterations in sepsis

et al. 2013

View full text Add to dashboard Cite

show abstract

“…In contrast to these findings, Tzepi et al (2012) recently reported in The Journal of Pharmacology and Experimental Therapeutics that systemic delivery of recombinant human angiopoietin-2 (rhAngpt-2), but not rhAngpt-1, improved survival in mice challenged with live pseudomonas. How are these findings to be reconciled with the existing literature and our current understanding of Angpt/Tie2 signaling?…”

Section: The Angiopoietin/tie2 Systemmentioning

confidence: 63%

“…Supraphysiologic concentrations of Angpt-2 appear to activate Tie2 in mice, as shown by Daly et al (2006). Measurement of Tie2 phosphorylation in the work by Tzepi et al (2012) would have added to our understanding of the molecular pathogenesis of pseudomonal bacteremia and to the underlying mechanism driving the benefit of rhAngpt-2 in this model.…”

Section: The Angiopoietin/tie2 Systemmentioning

confidence: 99%

“…The intriguing results of Tzepi et al (2012) could also reflect other putative mechanisms-e.g., stimulation of nonendothelial cells and/or signaling through non-Tie2 receptors (Felcht et al, 2012). In our opinion, the simplest test of whether Angpt-2 induction is pathogenic (or protective) in sepsis would target the endogenous protein by inhibiting its production, blocking its release, or neutralizing its effects.…”

Section: The Angiopoietin/tie2 Systemmentioning

confidence: 99%

“…Of numerous investigated pathways, only five randomized controlled clinical trials improved survival in septic patients about a decade ago (Brower et al, 2000;Bernard et al, 2001;Rivers et al, 2001;van den Berghe et al, 2001;Annane et al, 2002). Three of those have been disproven in larger studies, with activated protein C being the latest and most prominent candidate that was removed from the market in late 2011 (Ranieri et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Mending Leaky Blood Vessels: The Angiopoietin-Tie2 Pathway in Sepsis

David¹,

Kümpers

Slyke

et al. 2013

J Pharmacol Exp Ther

View full text Add to dashboard Cite

Sepsis is a systemic inflammatory response to infection. A common end-feature, these patients regularly suffer from is the so-called multiple organ dysfunction syndrome, an often fatal consequence of organ hypoperfusion, coagulopathy, immune dysregulation, and mitochondrial dysfunction. Microvascular dysfunction critically contributes to the morbidity and mortality of this disease. The angiopoietin (Angpt)/Tie2 system consists of the transmembrane endothelial tyrosine kinase Tie2 and its circulating ligands (Angpt-1, -2, and -3/4). The balance between the canonical agonist Angpt-1 and its competitive inhibitor, Angpt-2, regulates basal endothelial barrier function and the leakage and vascular inflammation that develop in response to pathogens and cytokines. Here we summarize recent work in mice and men to highlight the therapeutic potential in this pathway to prevent or even reverse microvascular dysfunction in this deadly disease.

show abstract

Hepatic changes in systemic infection

Srivastava

Gimson

2013

Best Practice & Research Clinical Gastroenterology

View full text Add to dashboard Cite

Angiopoietin-2 Enhances Survival in Experimental Sepsis Induced by Multidrug-ResistantPseudomonas aeruginosa

Cited by 20 publications

References 32 publications

Angiopoietin 2 mediates microvascular and hemodynamic alterations in sepsis

Angiopoietin 2 mediates microvascular and hemodynamic alterations in sepsis

Mending Leaky Blood Vessels: The Angiopoietin-Tie2 Pathway in Sepsis

Hepatic changes in systemic infection

Contact Info

Product

Resources

About