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J Immunol. 2013 Jun 15;190(12):6378-88. doi: 10.4049/jimmunol.1202969. Epub 2013 May 6.

Inhaled carbon monoxide accelerates resolution of inflammation via unique proresolving mediator-heme oxygenase-1 circuits.

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Department of Anesthesiology, Perioperative and Pain Medicine, Center for Experimental Therapeutics and Reperfusion Injury, Harvard Institutes of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.


Resolution of acute inflammation is an active event accompanied by biosynthesis of specialized proresolving mediators (SPM). We employed a systems approach to determine the impact of CO in resolution active programs during self-limited inflammation in mice. Compared with ambient air, inhaled CO gas (250 ppm) significantly limited PMN infiltration (∼44%, 6 h) into peritoneum and shortened resolution interval from 4 to 2 h. We profiled exudate lipid mediators (LM) via metabololipidomics, CO reduced leukotriene B4 (21 ± 11 versus 59 ± 24 pg/mouse, 6 h), and elevated SPM including resolvin (Rv) D1 (27 ± 4 versus 16 ± 5 pg/mouse) and maresin 1 (26 ± 9 versus 15 ± 3 pg/mouse). With human macrophages, SPM (10 pM-10 nM) elevated heme oxygenase (HO)-1 (∼50%, 8 h). CO also enhanced HO-1 expression and accumulation of RvD1 and RvD5, an action reversed by blockage of a key SPM biosynthesis enzyme 15-lipoxygenase type 1. Compared with normoxia, CO increased ∼30% phagocytosis of opsonized zymosan with human macrophage, which was further enhanced by SPM (∼100%). This CO increased phagocytosis was blocked by 15-lipoxygenase inhibition, and SPM stimulated phagocytosis was diminished by HO-1 inhibition. In murine peritonitis, both pre- and posttreatment with CO inhalation significantly increased macrophages carrying ingested apoptotic PMN in exudates and enhanced PMN apoptosis. Taken together, these results indicate that CO accelerates resolution of acute inflammation, shortens resolution intervals, enhances macrophage efferocytosis, and temporally regulates local levels of lipid mediator/SPM. Moreover, they provide proresolving mechanisms for HO-1/CO, which is part of the SPM-initiated resolution circuit.

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