Publication Date:
2012-04-28
Description:
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-kappaB and TNF-alpha. 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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3340015/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3340015/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chiang, Nan -- Fredman, Gabrielle -- Backhed, Fredrik -- Oh, Sungwhan F -- Vickery, Thad -- Schmidt, Birgitta A -- Serhan, Charles N -- P01 GM095467/GM/NIGMS NIH HHS/ -- P01 GM095467-01/GM/NIGMS NIH HHS/ -- P01 GM095467-02/GM/NIGMS NIH HHS/ -- P01GM095467/GM/NIGMS NIH HHS/ -- R01 GM038765/GM/NIGMS NIH HHS/ -- R01 GM038765-24/GM/NIGMS NIH HHS/ -- R01 GM038765-25/GM/NIGMS NIH HHS/ -- R01 GM038765-26/GM/NIGMS NIH HHS/ -- R01GM38765/GM/NIGMS NIH HHS/ -- England -- Nature. 2012 Apr 25;484(7395):524-8. doi: 10.1038/nature11042.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉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.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22538616" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Anti-Bacterial Agents/*pharmacology/therapeutic use
;
Docosahexaenoic Acids/*metabolism
;
Escherichia coli/*drug effects/immunology
;
Escherichia coli Infections/drug therapy/*metabolism/microbiology
;
Humans
;
Hypothermia/prevention & control
;
Macrophages/immunology
;
Male
;
Mice
;
Mice, Inbred C57BL
;
Microbial Viability/drug effects
;
Neutrophils/immunology
;
Peritonitis/drug therapy/metabolism/microbiology
;
Phagocytosis
;
Skin Diseases/drug therapy/metabolism/microbiology
;
Staphylococcal Infections/drug therapy/*metabolism/microbiology
;
Staphylococcus aureus/drug effects/immunology
;
Vancomycin/pharmacology/therapeutic use
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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