Infection regulates pro-resolving mediators that lower antibiotic requirements.
Infection regulates pro-resolving mediators that lower antibiotic requirements.
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DOI：
10.1038/nature11042
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发表时间：
2012-04-25
期刊：
影响因子：
64.8
通讯作者：
Serhan, Charles N.
中科院分区：
文献类型：
--
作者：
Chiang, Nan;Fredman, Gabrielle;Backhed, Fredrik;Oh, Sungwhan F.;Vickery, Thad;Schmidt, Birgitta A.;Serhan, Charles N.
细菌感染如何促进急性炎症的主动消退的潜在机制尚不清楚。在这里，我们进行渗出液白细胞运输和介体代谢脂质组学的小鼠腹膜大肠杆菌（E。大肠杆菌）感染与时间鉴定的促炎性（白藜芦醇和白三烯）和专门的前解决介质（SPM）。在自分辨E.大肠杆菌分泌物（105 CFU）中，主要的SPM是Resolvin（Rv）D5和Protectin D1（PD1），在12 h时，其水平显著高于高滴度大肠杆菌分泌物中的水平。coli（107 CFU）攻击的小鼠。无菌小鼠显示内源性RvD1和PD1水平高于常规小鼠。RvD1和RvD5（ng/mouse）各自降低血液和渗出液中的细菌滴度，E.大肠杆菌诱导的体温过低和增加的存活，证明了RvD5的第一个作用。RvD1、RvD5和PD1分别直接增强人多形核中性粒细胞（PMN）和巨噬细胞对E.大肠杆菌，和RvD5反调节一组促炎基因，包括NF-κ B和TNF-α。RvD5激活RvD1受体GPR32以增强吞噬作用。自限性E.大肠杆菌感染，RvD1和抗生素环丙沙星加速消退，每缩短分辨率间隔（Ri）。宿主导向的RvD1作用增强了环丙沙星的治疗作用。在107CFU E. SPM（RvD1、RvD5、PD1）与环丙沙星联用也能增强宿主的抗菌活性。在皮肤感染中，SPM增强万古霉素对金黄色葡萄球菌的清除。这些结果表明，特异性SPM在感染期间受到时间和差异性调节，并且它们是抗炎的，增强了遏制力并降低了细菌清除的抗生素需求。
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 (E. coli) infections with temporal identification of pro-inflammatory (prostaglandins and leukotrienes) and specialized pro-resolving mediators (SPM). In self-resolving E. coli exudates (105 CFU), the dominant SPM identified were resolvin (Rv) D5 and protectin D1 (PD1), which at 12 h were significantly greater than levels in exudates from higher titer E. coli (107 CFU) challenged mice. Germ-free mice displayed endogenous RvD1 and PD1 levels higher than in conventional mice. RvD1 and RvD5 (ng/mouse) each reduced bacterial titers in blood and exudates, E. coli-induced hypothermia and increased survival, demonstrating the first actions of RvD5. With human polymorphonuclear neutrophils (PMN) 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 (Ri). Host-directed RvD1 actions enhanced ciprofloxacin’s therapeutic actions. In 107 CFU E. coli infections, SPM (RvD1, RvD5, PD1) together with ciprofloxacin also heightened host antimicrobial responses. In skin infections, SPM enhanced vancomycin clearance of Staphylococcus aureus. These results demonstrate that specific SPM are temporally and differentially regulated during infections and that they are anti-phlogistic, enhance containment and lower antibiotic requirements for bacterial clearance.
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影响因子：
20.3
作者：
Stables, Melanie J.;Newson, Justine;Gilroy, Derek W.
通讯作者：
Gilroy, Derek W.
影响因子：
5.4
作者：
Schif-Zuck, Sagie;Gross, Nufar;Assi, Simaan;Rostoker, Ran;Serhan, Charles N.;Ariel, Amiram
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影响因子：
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作者：
Dinarello CA
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腺病毒递送的血管生成素1加速小鼠急性内毒素性肺损伤炎症的消退
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5.7
作者：
Xu, You-Nian;Zhang, Zhao;Zhang, Shi-Hai
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Zhang, Shi-Hai
影响因子：
15.9
作者：
Oh, Sungwhan F.;Pillai, Padmini S.;Serhan, Charles N.
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Serhan, Charles N.