title: Asymmetric dimethylarginine in chronic obstructive pulmonary disease (ADMA in COPD).
abstract: L-arginine metabolism including the nitric oxide (NO) synthase and arginase pathways is important in the maintenance of airways function. We have previously reported that accumulation of asymmetric dimethylarginine (ADMA) in airways, resulting in changes in L-arginine metabolism, contributes to airways obstruction in asthma and cystic fibrosis. Herein, we assessed L-arginine metabolism in airways of patients with chronic obstructive pulmonary disease (COPD). Lung function testing, measurement of fractional exhaled NO (FeNO) and sputum NO metabolites, as well as quantification of L-arginine metabolites (L-arginine, L-ornithine, L-citrulline, ADMA and symmetric dimethylarginine) using liquid chromatography-mass spectrometry (LC-MS) were performed. Concentrations of L-ornithine, the product of arginase activity, correlated directly with L-arginine and ADMA sputum concentrations. FeNO correlated directly with pre- and post-bronchodilator forced expiratory volume in one second (FEV1). Sputum arginase activity correlated inversely with total NO metabolite (NOx) and nitrite concentrations in sputum, and with pre- and post-bronchodilator FEV1. These findings suggest that ADMA in COPD airways results in a functionally relevant shift of L-arginine breakdown by the NO synthases towards the arginase pathway, which contributes to airway obstruction in these patients.
authors.affiliation: Department of Health Sciences, Lakehead University, 955 Oliver Road, Thunder Bay, ON P7B 5E1, Canada. jascott1@lakeheadu.ca.
authors.forename: Jeremy A
authors.initials: JA
authors.lastname: Scott
authors.affiliation: Department of Medicine, McMaster University, 1280 Main Street West, Hamilton, ON L8S 4L8, Canada. duongmy@mcmaster.ca.
authors.forename: MyLinh
authors.initials: M
authors.lastname: Duongh
authors.affiliation: Department of Physiology and Biophysics, Boston University School of Medicine, 72 East Concord St., Boston, MA 02118, USA. youngaw@bu.edu.
authors.forename: Aaron W
authors.initials: AW
authors.lastname: Young
authors.affiliation: Program in Physiology and Experimental Medicine, SickKids Research Institute, and Division of Respiratory Medicine, Department of Pediatrics, Hospital for Sick Children, 555 University Avenue University of Toronto, Toronto, ON M5G 1X8, Canada. padmaja.subbarao@sickkids.ca.
authors.forename: Padmaja
authors.initials: P
authors.lastname: Subbarao
authors.affiliation: Department of Medicine, McMaster University, 1280 Main Street West, Hamilton, ON L8S 4L8, Canada. gauvreau@mcmaster.ca.
authors.forename: Gail M
authors.initials: GM
authors.lastname: Gauvreau
authors.affiliation: Program in Physiology and Experimental Medicine, SickKids Research Institute, and Division of Respiratory Medicine, Department of Pediatrics, Hospital for Sick Children, 555 University Avenue University of Toronto, Toronto, ON M5G 1X8, Canada. hartmut.grasemann@sickkids.ca.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Grasemann
mesh_terms: D000368:Aged; D001119:Arginase / Q000378:metabolism; D001120:Arginine / Q000031:analogs & derivatives* / Q000032:analysis / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D005260:Female; D005541:Forced Expiratory Volume; D006801:Humans; D008168:Lung / Q000502:physiology; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D009952:Ornithine / Q000032:analysis; D029424:Pulmonary Disease, Chronic Obstructive / Q000378:metabolism* / Q000473:pathology; D013183:Sputum / Q000201:enzymology; D053719:Tandem Mass Spectrometry
chemical_list: D009569:Nitric Oxide; C018524:N,N-dimethylarginine; D001120:Arginine; D009952:Ornithine; D019001:Nitric Oxide Synthase; D001119:Arginase
references.citation: J Pharmacol Exp Ther. 2014 May;349(2):229-38
references.pmid: 24563530
references.citation: BMC Pulm Med. 2009 Jan 29;9:5
references.pmid: 19178698
references.citation: Pharmacol Res. 2009 Dec;60(6):481-7
references.pmid: 19596069
references.citation: Chest. 2013 Aug;144(2):367-368
references.pmid: 23918098
references.citation: Trends Pharmacol Sci. 2003 Sep;24(9):450-5
references.pmid: 12967769
references.citation: Biochim Biophys Acta. 2011 Nov;1810(11):1017-24
references.pmid: 21718756
references.citation: J Clin Invest. 2003 Jun;111(12):1863-74
references.pmid: 12813022
references.citation: Pharmacol Res. 2009 Dec;60(6):508-14
references.pmid: 19651212
references.citation: Lancet. 1992 Mar 7;339(8793):572-5
references.pmid: 1347093
references.citation: Am J Physiol Lung Cell Mol Physiol. 2009 Jun;296(6):L911-20
references.pmid: 19286931
references.citation: Nat Rev Nephrol. 2011 May;7(5):275-85
references.pmid: 21445101
references.citation: J Allergy Clin Immunol. 2007 Feb;119(2):391-7
references.pmid: 17291856
references.citation: Am J Respir Crit Care Med. 2013 Jan 15;187(2):153-9
references.pmid: 23204252
references.citation: PLoS One. 2012;7(10):e46618
references.pmid: 23071598
references.citation: Am J Respir Cell Mol Biol. 2011 May;44(5):673-81
references.pmid: 20595463
references.citation: Am J Respir Crit Care Med. 2013 Feb 15;187(4):347-65
references.pmid: 22878278
references.citation: Am J Respir Cell Mol Biol. 2013 Jun;48(6):694-702
references.pmid: 23470627
references.citation: Am J Respir Crit Care Med. 1994 Feb;149(2 Pt 1):538-51
references.pmid: 7508323
references.citation: J Investig Med. 2011 Mar;59(3):587-92
references.pmid: 21245771
references.citation: Am J Respir Crit Care Med. 2005 Apr 15;171(8):912-30
references.pmid: 15817806
references.citation: Am J Physiol Lung Cell Mol Physiol. 2008 Mar;294(3):L489-97
references.pmid: 17675371
references.citation: Am J Respir Crit Care Med. 2011 Oct 1;184(7):779-85
references.pmid: 21719758
references.citation: Am J Respir Crit Care Med. 2005 Dec 15;172(12):1523-8
references.pmid: 16166623
references.citation: Eur Respir J. 2005 Jul;26(1):1-2
references.pmid: 15994380
references.citation: Am J Respir Crit Care Med. 2008 Oct 1;178(7):673-81
references.pmid: 18635886
references.citation: Naunyn Schmiedebergs Arch Pharmacol. 2008 Aug;378(2):171-84
references.pmid: 18437360
references.citation: J Cyst Fibros. 2013 Sep;12(5):468-74
references.pmid: 23333044
references.citation: Respir Med. 2013 Dec;107(12):1895-903
references.pmid: 23993707
references.citation: Am J Respir Crit Care Med. 2011 Sep 1;184(5):602-15
references.pmid: 21885636
references.citation: Inflamm Res. 2001 Dec;50(12):616-24
references.pmid: 11822788
references.citation: Eur J Pharmacol. 2008 May 13;585(2-3):375-84
references.pmid: 18410920
references.citation: Br J Pharmacol. 2002 Jun;136(3):391-8
references.pmid: 12023942
references.citation: Chest. 2013 Jan;143(1):107-116
references.pmid: 22628492
references.citation: Nestle Nutr Inst Workshop Ser. 2013;77:1-15
references.pmid: 24107492
references.citation: Eur J Pharmacol. 2006 Mar 8;533(1-3):253-62
references.pmid: 16458291
references.citation: Am J Respir Crit Care Med. 2011 May 15;183(10):1363-8
references.pmid: 21278301