title: Angiopoietin-2 enhances survival in experimental sepsis induced by multidrug-resistant Pseudomonas aeruginosa.
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.
authors.affiliation: Fourth Department of Internal Medicine, University of Athens Medical School, Attikon University Hospital, 1 Rimini Str, 124 62 Athens, Greece.
authors.forename: Ira-Maria
authors.initials: IM
authors.lastname: Tzepi
authors.forename: Evangelos J
authors.initials: EJ
authors.lastname: Giamarellos-Bourboulis
authors.forename: Dionyssia-Pinelopi
authors.initials: DP
authors.lastname: Carrer
authors.forename: Thomas
authors.initials: T
authors.lastname: Tsaganos
authors.forename: Ralf A
authors.initials: RA
authors.lastname: Claus
authors.forename: Ilia
authors.initials: I
authors.lastname: Vaki
authors.forename: Aimilia
authors.initials: A
authors.lastname: Pelekanou
authors.forename: Antigone
authors.initials: A
authors.lastname: Kotsaki
authors.forename: Vassiliki
authors.initials: V
authors.lastname: Tziortzioti
authors.forename: Stavros
authors.initials: S
authors.lastname: Topouzis
authors.forename: Michael
authors.initials: M
authors.lastname: Bauer
authors.forename: Andreas
authors.initials: A
authors.lastname: Papapetropoulos
mesh_terms: D042702:Angiopoietin-2 / Q000627:therapeutic use*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002199:Capillary Permeability / Q000187:drug effects; D002452:Cell Count; D003114:Colony-Forming Units Assay; D016207:Cytokines / Q000096:biosynthesis; D024901:Drug Resistance, Multiple, Bacterial; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D004926:Escherichia coli / Q000187:drug effects; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000187:drug effects; D010529:Peritoneal Cavity / Q000166:cytology; D011552:Pseudomonas Infections / Q000188:drug therapy* / Q000382:microbiology / Q000473:pathology; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000472:pathogenicity; D018805:Sepsis / Q000188:drug therapy* / Q000382:microbiology / Q000473:pathology; D013154:Spleen / Q000166:cytology / Q000378:metabolism; D016019:Survival Analysis; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D020298:U937 Cells
chemical_list: D042702:Angiopoietin-2; D016207:Cytokines; D004791:Enzyme Inhibitors; D014409:Tumor Necrosis Factor-alpha