title: Inhaled carbon monoxide accelerates resolution of inflammation via unique proresolving mediator-heme oxygenase-1 circuits.
abstract: 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.
authors: 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.
authors: Nan
authors: N
authors: Chiang
authors: Masakazu
authors: M
authors: Shinohara
authors: Jesmond
authors: J
authors: Dalli
authors: Valbona
authors: V
authors: Mirakaj
authors: Megumi
authors: M
authors: Kibi
authors: Augustine M K
authors: AM
authors: Choi
authors: Charles N
authors: CN
authors: Serhan
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D002248:Carbon Monoxide / Q000008:administration & dosage*; D002478:Cells, Cultured; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000276:immunology*; D018836:Inflammation Mediators / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051379:Mice; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*
chemical_list: D018836:Inflammation Mediators; D002248:Carbon Monoxide; D051547:Heme Oxygenase-1
references: Proc Natl Acad Sci U S A. 2012 Sep 11;109(37):14983-8
references: 22927428
references: Anesth Analg. 2011 Jun;112(6):1403-10
references: 21543779
references: J Biol Chem. 1993 May 5;268(13):9376-80
references: 8486631
references: J Biol Chem. 2007 Mar 30;282(13):9323-9334
references: 17244615
references: J Immunol. 2010 Feb 1;184(3):1516-25
references: 20032295
references: Nat Rev Immunol. 2013 Jan;13(1):59-66
references: 23197111
references: FASEB J. 2007 Jul;21(9):2257-66
references: 17384141
references: Cell. 2010 Mar 19;140(6):771-6
references: 20303867
references: Nature. 2007 Jun 14;447(7146):869-74
references: 17568749
references: Am J Physiol Lung Cell Mol Physiol. 2010 Dec;299(6):L891-7
references: 20729385
references: Mol Pharmacol. 1987 Oct;32(4):497-504
references: 2890093
references: J Immunol. 2008 Mar 1;180(5):3512-9
references: 18292578
references: Sci Signal. 2009 Apr 28;2(68):re2
references: 19401594
references: PLoS One. 2008 Apr 02;3(4):e1879
references: 18382663
references: J Biol Chem. 2006 Aug 11;281(32):22847-54
references: 16757471
references: Antioxid Redox Signal. 2012 Jul 1;17(1):58-67
references: 22017247
references: Annu Rev Immunol. 2007;25:101-37
references: 17090225
references: FASEB J. 2011 Feb;25(2):544-60
references: 20956612
references: J Pharmacol Exp Ther. 2007 May;321(2):656-62
references: 17289832
references: Chem Rev. 2011 Oct 12;111(10):5922-43
references: 21766791
references: Br J Pharmacol. 2006 Jan;147 Suppl 1:S193-201
references: 16402104
references: Methods Mol Biol. 2000;99:369-91
references: 10909094
references: J Biol Chem. 1996 Sep 27;271(39):24055-62
references: 8798642
references: Thromb Haemost. 1982 Dec 27;48(3):286-8
references: 7164019
references: Proc Natl Acad Sci U S A. 2010 Jan 26;107(4):1660-5
references: 20080636
references: Am J Physiol Cell Physiol. 2005 Sep;289(3):C557-63
references: 15901601
references: J Biol Chem. 1984 Aug 25;259(16):10181-7
references: 6088485
references: J Exp Med. 2000 Oct 16;192(8):1197-204
references: 11034610
references: J Exp Med. 1996 Jan 1;183(1):137-46
references: 8551217
references: Anesth Analg. 2007 Feb;104(2):369-77
references: 17242094
references: Pharmacol Rev. 2008 Mar;60(1):79-127
references: 18323402
references: Am J Surg. 2012 Apr;203(4):488-95
references: 22450026
references: Nature. 2012 Apr 25;484(7395):524-8
references: 22538616
references: Cell. 2010 Mar 19;140(6):871-82
references: 20303877
references: Nat Immunol. 2008 Aug;9(8):873-9
references: 18568027
references: Biochem Biophys Res Commun. 1982 Apr 14;105(3):1090-5
references: 6807310
references: J Biol Chem. 2003 Apr 25;278(17):14677-87
references: 12590139
references: Cell. 2010 Mar 19;140(6):935-50
references: 20303881
references: Blood. 2012 Oct 11;120(15):e60-72
references: 22904297
references: Clin Exp Rheumatol. 2012 Jan-Feb;30(1):73-8
references: 22325451