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, Andreas Papapetropoulos

Research output: Contribution to journalArticle

15 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)278-287
Number of pages10
JournalJournal of Pharmacology and Experimental Therapeutics
Volume343
Issue number2
DOIs
StatePublished - Nov 1 2012
Externally publishedYes

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Angiopoietin-2
Pseudomonas aeruginosa
Sepsis
Tumor Necrosis Factor-alpha
Neutrophil Infiltration
Lipopolysaccharides
Interleukin-6
U937 Cells
Interleukin-10

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

Angiopoietin-2 enhances survival in experimental sepsis induced by multidrug-resistant Pseudomonas aeruginosa. / Tzepi, Ira Maria; Giamarellos-Bourboulis, Evangelos J.; Carrer, Dionyssia Pinelopi; Tsaganos, Thomas; Claus, Ralf A.; Vaki, Ilia; Pelekanou, Aimilia; Kotsaki, Antigone; Tziortzioti, Vassiliki; Topouzis, Stavros; Bauer, Michael; Papapetropoulos, Andreas.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 343, No. 2, 01.11.2012, p. 278-287.

Research output: Contribution to journalArticle

Tzepi, IM, Giamarellos-Bourboulis, EJ, Carrer, DP, Tsaganos, T, Claus, RA, Vaki, I, Pelekanou, A, Kotsaki, A, Tziortzioti, V, Topouzis, S, Bauer, M & Papapetropoulos, A 2012, 'Angiopoietin-2 enhances survival in experimental sepsis induced by multidrug-resistant Pseudomonas aeruginosa', Journal of Pharmacology and Experimental Therapeutics, vol. 343, no. 2, pp. 278-287. https://doi.org/10.1124/jpet.112.195180
Tzepi, Ira Maria ; Giamarellos-Bourboulis, Evangelos J. ; Carrer, Dionyssia Pinelopi ; Tsaganos, Thomas ; Claus, Ralf A. ; Vaki, Ilia ; Pelekanou, Aimilia ; Kotsaki, Antigone ; Tziortzioti, Vassiliki ; Topouzis, Stavros ; Bauer, Michael ; Papapetropoulos, Andreas. / Angiopoietin-2 enhances survival in experimental sepsis induced by multidrug-resistant Pseudomonas aeruginosa. In: Journal of Pharmacology and Experimental Therapeutics. 2012 ; Vol. 343, No. 2. pp. 278-287.
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