title: Infection regulates pro-resolving mediators that lower antibiotic requirements.
abstract: Underlying mechanisms for how bacterial infections contribute to active resolution of acute inflammation are unknown. Here, we performed exudate leukocyte trafficking and mediator-metabololipidomics of murine peritoneal Escherichia coli infections with temporal identification of pro-inflammatory (prostaglandins and leukotrienes) and specialized pro-resolving mediators (SPMs). In self-resolving E. coli exudates (10(5) colony forming units, c.f.u.), the dominant SPMs identified were resolvin (Rv) D5 and protectin D1 (PD1), which at 12 h were at significantly greater levels than in exudates from higher titre E. coli (10(7) c.f.u.)-challenged mice. Germ-free mice had endogenous RvD1 and PD1 levels higher than in conventional mice. RvD1 and RvD5 (nanograms per mouse) each reduced bacterial titres in blood and exudates, E. coli-induced hypothermia and increased survival, demonstrating the first actions of RvD5. With human polymorphonuclear neutrophils and macrophages, RvD1, RvD5 and PD1 each directly enhanced phagocytosis of E. coli, and RvD5 counter-regulated a panel of pro-inflammatory genes, including NF-κB and TNF-α. RvD5 activated the RvD1 receptor, GPR32, to enhance phagocytosis. With self-limited E. coli infections, RvD1 and the antibiotic ciprofloxacin accelerated resolution, each shortening resolution intervals (R(i)). Host-directed RvD1 actions enhanced ciprofloxacin's therapeutic actions. In 10(7) c.f.u. E. coli infections, SPMs (RvD1, RvD5, PD1) together with ciprofloxacin also heightened host antimicrobial responses. In skin infections, SPMs enhanced vancomycin clearance of Staphylococcus aureus. These results demonstrate that specific SPMs are temporally and differentially regulated during infections and that they are anti-phlogistic, enhance containment and lower antibiotic requirements for bacterial clearance.
authors.affiliation: Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Nan
authors.initials: N
authors.lastname: Chiang
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Fredman
authors.forename: Fredrik
authors.initials: F
authors.lastname: Bäckhed
authors.forename: Sungwhan F
authors.initials: SF
authors.lastname: Oh
authors.forename: Thad
authors.initials: T
authors.lastname: Vickery
authors.forename: Birgitta A
authors.initials: BA
authors.lastname: Schmidt
authors.forename: Charles N
authors.initials: CN
authors.lastname: Serhan
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology* / Q000627:therapeutic use; D004281:Docosahexaenoic Acids / Q000378:metabolism*; D004926:Escherichia coli / Q000187:drug effects* / Q000276:immunology; D004927:Escherichia coli Infections / Q000188:drug therapy / Q000378:metabolism* / Q000382:microbiology; D006801:Humans; D007035:Hypothermia / Q000517:prevention & control; D008264:Macrophages / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D050296:Microbial Viability / Q000187:drug effects; D009504:Neutrophils / Q000276:immunology; D010538:Peritonitis / Q000188:drug therapy / Q000378:metabolism / Q000382:microbiology; D010587:Phagocytosis; D012871:Skin Diseases / Q000188:drug therapy / Q000378:metabolism / Q000382:microbiology; D013203:Staphylococcal Infections / Q000188:drug therapy / Q000378:metabolism* / Q000382:microbiology; D013211:Staphylococcus aureus / Q000187:drug effects / Q000276:immunology; D014640:Vancomycin / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000900:Anti-Bacterial Agents; C487679:protectin D1; C518399:resolvin D1; C572765:resolvin D5; D004281:Docosahexaenoic Acids; D014640:Vancomycin