title: Cell-cell interactions and bronchoconstrictor eicosanoid reduction with inhaled carbon monoxide and resolvin D1.
abstract: Polymorphonuclear leukocyte (PMN)-mediated acute lung injury from ischemia/reperfusion (I/R) remains a major cause of morbidity and mortality in critical care medicine. Here, we report that inhaled low-dose carbon monoxide (CO) and intravenous resolvin D1 (RvD1) in mice each reduced PMN-mediated acute lung injury from I/R. Inhaled CO (125-250 ppm) and RvD1 (250-500 ng) each reduced PMN lung infiltration and gave additive lung protection. In mouse whole blood, CO and RvD1 attenuated PMN-platelet aggregates, reducing leukotrienes (LTs) and thromboxane B2 (TxB2) in I/R lungs. With human whole blood, CO (125-250 ppm) decreased PMN-platelet aggregates, expression of adhesion molecules, and cysteinyl LTs, as well as TxB2. RvD1 (1-100 nM) also dose dependently reduced platelet activating factor-stimulated PMN-platelet aggregates in human whole blood. In nonhuman primate (baboon) lung infection with Streptococcus pneumoniae, inhaled CO reduced urinary cysteinyl LTs. These results demonstrate lung protection by low-dose inhaled CO as well as RvD1 that each reduced PMN-mediated acute tissue injury, PMN-platelet interactions, and production of both cysteinyl LTs and TxB2. Together they suggest a potential therapeutic role of low-dose inhaled CO in organ protection, as demonstrated using mouse I/R-initiated lung injury, baboon infections, and human whole blood.
authors.affiliation: Center for Experimental Therapeutics and Reperfusion Injury, Harvard Institutes of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts;
authors.forename: Masakazu
authors.initials: M
authors.lastname: Shinohara
authors.affiliation: Center for Experimental Therapeutics and Reperfusion Injury, Harvard Institutes of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts;
authors.forename: Megumi
authors.initials: M
authors.lastname: Kibi
authors.affiliation: Center for Experimental Therapeutics and Reperfusion Injury, Harvard Institutes of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts;
authors.forename: Ian R
authors.initials: IR
authors.lastname: Riley
authors.affiliation: Center for Experimental Therapeutics and Reperfusion Injury, Harvard Institutes of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts;
authors.forename: Nan
authors.initials: N
authors.lastname: Chiang
authors.affiliation: Center for Experimental Therapeutics and Reperfusion Injury, Harvard Institutes of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts;
authors.forename: Jesmond
authors.initials: J
authors.lastname: Dalli
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, North Carolina;
authors.forename: Bryan D
authors.initials: BD
authors.lastname: Kraft
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, North Carolina;
authors.forename: Claude A
authors.initials: CA
authors.lastname: Piantadosi
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; Division of Pulmonary and Critical Care Medicine, Weill Department of Medicine, Weill Cornell Medical College, New York, New York.
authors.forename: Augustine M K
authors.initials: AM
authors.lastname: Choi
authors.affiliation: Center for Experimental Therapeutics and Reperfusion Injury, Harvard Institutes of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; cnserhan@zeus.bwh.harvard.edu.
authors.forename: Charles N
authors.initials: CN
authors.lastname: Serhan
mesh_terms: D055371:Acute Lung Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology*; D002248:Carbon Monoxide / Q000494:pharmacology*; D002450:Cell Communication / Q000187:drug effects*; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism / Q000473:pathology; D015289:Leukotrienes / Q000378:metabolism*; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D010215:Papio; D011018:Pneumonia, Pneumococcal / Q000378:metabolism / Q000473:pathology; D013296:Streptococcus pneumoniae / Q000378:metabolism; D013929:Thromboxane B2 / Q000378:metabolism*
chemical_list: D000963:Antimetabolites; D015289:Leukotrienes; C518399:resolvin D1; D004281:Docosahexaenoic Acids; D013929:Thromboxane B2; D002248:Carbon Monoxide
keywords: ischemia/reperfusion; leukotrienes; lung; resolvins; thromboxane; transcellular eicosanoid biosynthesis