PT - JOURNAL ARTICLE AU - Ira-Maria Tzepi AU - Evangelos J. Giamarellos-Bourboulis AU - Dionyssia-Pinelopi Carrer AU - Thomas Tsaganos AU - Ralf A. Claus AU - Ilia Vaki AU - Aimilia Pelekanou AU - Antigone Kotsaki AU - Vassiliki Tziortzioti AU - Stavros Topouzis AU - Michael Bauer AU - Andreas Papapetropoulos TI - Angiopoietin-2 Enhances Survival in Experimental Sepsis Induced by Multidrug-Resistant <em>Pseudomonas aeruginosa</em> AID - 10.1124/jpet.112.195180 DP - 2012 Nov 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 278--287 VI - 343 IP - 2 4099 - http://jpet.aspetjournals.org/content/343/2/278.short 4100 - http://jpet.aspetjournals.org/content/343/2/278.full SO - J Pharmacol Exp Ther2012 Nov 01; 343 AB - 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.