RT Journal Article SR Electronic T1 Angiopoietin-2 Enhances Survival in Experimental Sepsis Induced by Multidrug-Resistant Pseudomonas aeruginosa JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 278 OP 287 DO 10.1124/jpet.112.195180 VO 343 IS 2 A1 Ira-Maria Tzepi A1 Evangelos J. Giamarellos-Bourboulis A1 Dionyssia-Pinelopi Carrer A1 Thomas Tsaganos A1 Ralf A. Claus A1 Ilia Vaki A1 Aimilia Pelekanou A1 Antigone Kotsaki A1 Vassiliki Tziortzioti A1 Stavros Topouzis A1 Michael Bauer A1 Andreas Papapetropoulos YR 2012 UL http://jpet.aspetjournals.org/content/343/2/278.abstract 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.