Aspirin-triggered resolvin D1 is produced during self-resolving gram-negative bacterial pneumonia and regulates host immune responses for the resolution of lung inflammation

被引:83
作者
Abdulnour, R. E. [1 ,2 ]
Sham, H. P. [1 ,2 ]
Douda, D. N. [1 ,2 ]
Colas, R. A. [2 ,3 ]
Dalli, J. [2 ,3 ]
Bai, Y. [1 ,2 ]
Ai, X. [1 ,2 ]
Serhan, C. N. [2 ,3 ]
Levy, B. D. [1 ,2 ,3 ]
机构
[1] Brigham & Womens Hosp, Dept Med, Pulm & Crit Care Med, 75 Francis St, Boston, MA 02115 USA
[2] Harvard Med Sch, Boston, MA 02115 USA
[3] Brigham & Womens Hosp, Ctr Expt Therapeut & Reperfus Injury, Dept Anesthesiol Perioperat & Pain Med, 75 Francis St, Boston, MA 02115 USA
基金
美国国家卫生研究院;
关键词
LIPID MEDIATORS; INFECTION; MACROPHAGES; MECHANISMS; PROMOTE; DISEASE; PHASE; CELLS; ACID;
D O I
10.1038/mi.2015.129
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Bacterial pneumonia is a leading cause of morbidity and mortality worldwide. Host responses to contain infection and mitigate pathogen-mediated lung inflammation are critical for pneumonia resolution. Aspirin-triggered resolvin D1 (AT-RvD1; 7S, 8R, 17R-trihydroxy-4Z, 9E, 11E, 13Z, 15E, 19Z-docosahexaenoic acid) is a lipid mediator (LM) that displays organ-protective actions in sterile lung inflammation, and regulates pathogen-initiated cellular responses. Here, in a self-resolving murine model of Escherichia coli pneumonia, LM metabololipidomics performed on lungs obtained at baseline, 24, and 72 h after infection uncovered temporal regulation of endogenous AT-RvD1 production. Early treatment with exogenous AT-RvD1 (1 h post infection) enhanced clearance of E. coli and Pseudomonas aeruginosa in vivo, and lung macrophage phagocytosis of fluorescent bacterial particles ex vivo. Characterization of macrophage subsets in the alveolar compartment during pneumonia identified efferocytosis by infiltrating macrophages (CD11b(Hi) CD11c(Low)) and exudative macrophages (CD11b(Hi) CD11c(Hi)). AT-RvD1 increased efferocytosis by these cells ex vivo, and accelerated neutrophil clearance during pneumonia in vivo. These anti-bacterial and pro-resolving actions of AT-RvD1 were additive to antibiotic therapy. Taken together, these findings suggest that the pro-resolving actions of AT-RvD1 during pneumonia represent a novel host-directed therapeutic strategy to complement the current antibiotic-centered approach for combatting infections.
引用
收藏
页码:1278 / 1287
页数:10
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