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Research ArticleInflammation, Immunopharmacology, and Asthma

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

Ira-Maria Tzepi, Evangelos J. Giamarellos-Bourboulis, Dionyssia-Pinelopi Carrer, Thomas Tsaganos, Ralf A. Claus, Ilia Vaki, Aimilia Pelekanou, Antigone Kotsaki, Vassiliki Tziortzioti, Stavros Topouzis, Michael Bauer and Andreas Papapetropoulos
Journal of Pharmacology and Experimental Therapeutics November 2012, 343 (2) 278-287; DOI: https://doi.org/10.1124/jpet.112.195180
Ira-Maria Tzepi
Fourth Department of Internal Medicine, University of Athens Medical School, Athens, Greece (I.-M.T., E.J.G.-B., D.-P.C., T.T., I.V., A.P., A.K., V.T.); Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany (E.J.G.-B., R.A.C., M.B.); and Department of Molecular Pharmacology, School of Pharmacy, University of Patras, Patras, Greece (S.T., A.P.)
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Evangelos J. Giamarellos-Bourboulis
Fourth Department of Internal Medicine, University of Athens Medical School, Athens, Greece (I.-M.T., E.J.G.-B., D.-P.C., T.T., I.V., A.P., A.K., V.T.); Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany (E.J.G.-B., R.A.C., M.B.); and Department of Molecular Pharmacology, School of Pharmacy, University of Patras, Patras, Greece (S.T., A.P.)
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Dionyssia-Pinelopi Carrer
Fourth Department of Internal Medicine, University of Athens Medical School, Athens, Greece (I.-M.T., E.J.G.-B., D.-P.C., T.T., I.V., A.P., A.K., V.T.); Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany (E.J.G.-B., R.A.C., M.B.); and Department of Molecular Pharmacology, School of Pharmacy, University of Patras, Patras, Greece (S.T., A.P.)
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Thomas Tsaganos
Fourth Department of Internal Medicine, University of Athens Medical School, Athens, Greece (I.-M.T., E.J.G.-B., D.-P.C., T.T., I.V., A.P., A.K., V.T.); Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany (E.J.G.-B., R.A.C., M.B.); and Department of Molecular Pharmacology, School of Pharmacy, University of Patras, Patras, Greece (S.T., A.P.)
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Ralf A. Claus
Fourth Department of Internal Medicine, University of Athens Medical School, Athens, Greece (I.-M.T., E.J.G.-B., D.-P.C., T.T., I.V., A.P., A.K., V.T.); Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany (E.J.G.-B., R.A.C., M.B.); and Department of Molecular Pharmacology, School of Pharmacy, University of Patras, Patras, Greece (S.T., A.P.)
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Ilia Vaki
Fourth Department of Internal Medicine, University of Athens Medical School, Athens, Greece (I.-M.T., E.J.G.-B., D.-P.C., T.T., I.V., A.P., A.K., V.T.); Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany (E.J.G.-B., R.A.C., M.B.); and Department of Molecular Pharmacology, School of Pharmacy, University of Patras, Patras, Greece (S.T., A.P.)
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Aimilia Pelekanou
Fourth Department of Internal Medicine, University of Athens Medical School, Athens, Greece (I.-M.T., E.J.G.-B., D.-P.C., T.T., I.V., A.P., A.K., V.T.); Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany (E.J.G.-B., R.A.C., M.B.); and Department of Molecular Pharmacology, School of Pharmacy, University of Patras, Patras, Greece (S.T., A.P.)
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Antigone Kotsaki
Fourth Department of Internal Medicine, University of Athens Medical School, Athens, Greece (I.-M.T., E.J.G.-B., D.-P.C., T.T., I.V., A.P., A.K., V.T.); Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany (E.J.G.-B., R.A.C., M.B.); and Department of Molecular Pharmacology, School of Pharmacy, University of Patras, Patras, Greece (S.T., A.P.)
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Vassiliki Tziortzioti
Fourth Department of Internal Medicine, University of Athens Medical School, Athens, Greece (I.-M.T., E.J.G.-B., D.-P.C., T.T., I.V., A.P., A.K., V.T.); Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany (E.J.G.-B., R.A.C., M.B.); and Department of Molecular Pharmacology, School of Pharmacy, University of Patras, Patras, Greece (S.T., A.P.)
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Stavros Topouzis
Fourth Department of Internal Medicine, University of Athens Medical School, Athens, Greece (I.-M.T., E.J.G.-B., D.-P.C., T.T., I.V., A.P., A.K., V.T.); Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany (E.J.G.-B., R.A.C., M.B.); and Department of Molecular Pharmacology, School of Pharmacy, University of Patras, Patras, Greece (S.T., A.P.)
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Michael Bauer
Fourth Department of Internal Medicine, University of Athens Medical School, Athens, Greece (I.-M.T., E.J.G.-B., D.-P.C., T.T., I.V., A.P., A.K., V.T.); Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany (E.J.G.-B., R.A.C., M.B.); and Department of Molecular Pharmacology, School of Pharmacy, University of Patras, Patras, Greece (S.T., A.P.)
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Andreas Papapetropoulos
Fourth Department of Internal Medicine, University of Athens Medical School, Athens, Greece (I.-M.T., E.J.G.-B., D.-P.C., T.T., I.V., A.P., A.K., V.T.); Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany (E.J.G.-B., R.A.C., M.B.); and Department of Molecular Pharmacology, School of Pharmacy, University of Patras, Patras, Greece (S.T., A.P.)
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Abstract

Levels of circulating angiopoietin-2 (Ang-2) increase in sepsis, raising the possibility that Ang-2 acts as a modulator in the sepsis cascade. To investigate this, experimental sepsis was induced in male C57BL6 mice by a multidrug-resistant isolate of Pseudomonas aeruginosa; survival was determined along with neutrophil tissue infiltration and release of proinflammatory cytokines. Survival was significantly increased either by pretreatment with recombinant Ang-2 2 h before or treatment with recombinant Ang-2 30 min after bacterial challenge. Likewise, Ang-2 pretreatment protected against sepsis-related death elicited by Escherichia coli; however, Ang-2 failed to provide protection in lipopolysaccharide (LPS)-challenged mice. The survival advantage of Ang-2 in response to P. aeruginosa challenge was lost in tumor necrosis factor (TNF)-deficient mice or neutropenic mice. Infiltration of the liver by neutrophils was elevated in the Ang-2 group compared with saline-treated animals. Serum TNF-α levels were reduced by Ang-2, whereas those of interleukin (IL)-6 and IL-10 remained unchanged. This was accompanied by lower release of TNF-α by stimulated splenocytes. When applied to U937 cells in vitro, heat-killed P. aeruginosa induced the secretion of IL-6 and TNF-α; low levels of exogenous TNF-α synergized with P. aeruginosa. This synergistic effect was abolished after the addition of Ang-2. These results put in evidence a striking protective role of Ang-2 in experimental sepsis evoked by a multidrug-resistant isolate of P. aeruginosa attributed to modulation of TNF-α production and changes in neutrophil migration. The protective role of Ang-2 is shown when whole microorganisms are used and not LPS, suggesting complex interactions with the host immune response.

Footnotes

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    http://dx.doi.org/10.1124/jpet.112.195180.

  • ABBREVIATIONS:

    PAMP
    pathogen-associated molecular pattern
    Ang
    angiopoietin
    cfu
    colony-forming units
    IFN-γ
    interferon-γ
    IL
    interleukin
    LPS
    lipopolysaccharide
    MDR
    multidrug-resistant
    NS
    nonsignificant
    N/S
    normal saline
    PA
    Pseudomonas aeruginosa
    TREM-1
    triggering receptor expressed on myeloid cells-1
    sTREM-1
    soluble TREM-1
    TNF
    tumor necrosis factor.

  • Received April 6, 2012.
  • Accepted July 31, 2012.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 343 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 343, Issue 2
1 Nov 2012
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Research ArticleInflammation, Immunopharmacology, and Asthma

Angiopoietin-2 in Experimental Sepsis

Ira-Maria Tzepi, Evangelos J. Giamarellos-Bourboulis, Dionyssia-Pinelopi Carrer, Thomas Tsaganos, Ralf A. Claus, Ilia Vaki, Aimilia Pelekanou, Antigone Kotsaki, Vassiliki Tziortzioti, Stavros Topouzis, Michael Bauer and Andreas Papapetropoulos
Journal of Pharmacology and Experimental Therapeutics November 1, 2012, 343 (2) 278-287; DOI: https://doi.org/10.1124/jpet.112.195180

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Research ArticleInflammation, Immunopharmacology, and Asthma

Angiopoietin-2 in Experimental Sepsis

Ira-Maria Tzepi, Evangelos J. Giamarellos-Bourboulis, Dionyssia-Pinelopi Carrer, Thomas Tsaganos, Ralf A. Claus, Ilia Vaki, Aimilia Pelekanou, Antigone Kotsaki, Vassiliki Tziortzioti, Stavros Topouzis, Michael Bauer and Andreas Papapetropoulos
Journal of Pharmacology and Experimental Therapeutics November 1, 2012, 343 (2) 278-287; DOI: https://doi.org/10.1124/jpet.112.195180
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