{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T07:15:17Z","timestamp":1789802117012,"version":"4.0.1"},"reference-count":38,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2014,4,10]],"date-time":"2014-04-10T00:00:00Z","timestamp":1397088000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/3.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/ijms15046062","type":"journal-article","created":{"date-parts":[[2014,4,10]],"date-time":"2014-04-10T11:41:08Z","timestamp":1397130068000},"page":"6062-6071","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":40,"title":["Asymmetric Dimethylarginine in Chronic Obstructive Pulmonary Disease (ADMA in COPD)"],"prefix":"10.3390","volume":"15","author":[{"given":"Jeremy","family":"Scott","sequence":"first","affiliation":[{"name":"Department of Health Sciences, Lakehead University, 955 Oliver Road, Thunder Bay,  ON P7B 5E1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"MyLinh","family":"Duongh","sequence":"additional","affiliation":[{"name":"Department of Medicine, McMaster University, 1280 Main Street West, Hamilton, ON L8S 4L8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron","family":"Young","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics, Boston University School of Medicine,  72 East Concord St., Boston, MA 02118, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Padmaja","family":"Subbarao","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gail","family":"Gauvreau","sequence":"additional","affiliation":[{"name":"Department of Medicine, McMaster University, 1280 Main Street West, Hamilton, ON L8S 4L8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hartmut","family":"Grasemann","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2014,4,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"48","DOI":"10.2174\/1875042701103010048","article-title":"l-Arginine metabolism in the lung: Reciprocal regulation of the NOS and arginase pathways","volume":"3","author":"North","year":"2011","journal-title":"Open Nitric Oxide J"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1007\/s00210-008-0286-7","article-title":"Arginase and pulmonary diseases","volume":"378","author":"Maarsingh","year":"2008","journal-title":"Naunyn Schmiedebergs Arch. Pharmacol"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1363","DOI":"10.1164\/rccm.201012-1995OC","article-title":"Asymmetric dimethylarginine contributes to airway nitric oxide deficiency in patients with cystic fibrosis","volume":"183","author":"Grasemann","year":"2011","journal-title":"Am. J. Respir. Crit. Care Med"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1164\/rccm.201011-1810OC","article-title":"Asymmetric dimethylarginine is increased in asthma","volume":"184","author":"Scott","year":"2011","journal-title":"Am. J. Respir. Crit. Care Med"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1378\/chest.13-0480","article-title":"Asymmetric dimethylarginine: A disease marker for asthma?","volume":"144","author":"Scott","year":"2013","journal-title":"Chest"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1523","DOI":"10.1164\/rccm.200502-253OC","article-title":"Increased arginase activity in cystic fibrosis airways","volume":"172","author":"Grasemann","year":"2005","journal-title":"Am. J. Respir. Crit. Care Med"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"L911","DOI":"10.1152\/ajplung.00025.2009","article-title":"Functionally important role for arginase 1 in the airway hyperresponsiveness of asthma","volume":"296","author":"North","year":"2009","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1863","DOI":"10.1172\/JCI17912","article-title":"Dissection of experimental asthma with DNA microarray analysis identifies arginase in asthma pathogenesis","volume":"111","author":"Zimmermann","year":"2003","journal-title":"J. Clin. Investig"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1016\/j.ejphar.2005.12.047","article-title":"The arginine-arginase balance in asthma and lung inflammation","volume":"533","author":"Zimmermann","year":"2006","journal-title":"Eur. J. Pharmacol"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1164\/ajrccm.149.2.7508323","article-title":"The biology of nitrogen oxides in the airways","volume":"149","author":"Gaston","year":"1994","journal-title":"Am. J. Respir. Crit. Care Med"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1159\/000351365","article-title":"Arginine and asthma","volume":"77","author":"Morris","year":"2013","journal-title":"Nestle Nutr. Inst. Workshop Ser"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1038\/sj.bjp.0704725","article-title":"Increased arginase activity underlies allergen-induced deficiency of cNOS-derived nitric oxide and airway hyperresponsiveness","volume":"136","author":"Meurs","year":"2002","journal-title":"Br. J. Pharmacol"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1016\/S0165-6147(03)00227-X","article-title":"Arginase and asthma: Novel insights into nitric oxide homeostasis and airway hyperresponsiveness","volume":"24","author":"Meurs","year":"2003","journal-title":"Trends Pharmacol. Sci"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"20","DOI":"10.2174\/1875042701002020020","article-title":"Arginase in asthma\u2014Recent developments in animal and human studies","volume":"2","author":"North","year":"2010","journal-title":"Open Nitric Oxide J"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e46618","DOI":"10.1371\/journal.pone.0046618","article-title":"l-ornithine derived polyamines in cystic fibrosis airways","volume":"7","author":"Grasemann","year":"2012","journal-title":"PLoS One"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"694","DOI":"10.1165\/rcmb.2012-0323OC","article-title":"Increased ornithine-derived polyamines cause airway hyperresponsiveness in a mouse model of asthma","volume":"48","author":"North","year":"2013","journal-title":"Am. J. Respir. Cell. Mol. Biol"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1007\/PL00000243","article-title":"The effect of allergen-induced airway inflammation on airway remodeling in a murine model of allergic asthma","volume":"50","author":"Tanaka","year":"2001","journal-title":"Inflamm. Res"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1164\/rccm.201207-1270OC","article-title":"An association between l-arginine\/asymmetric dimethyl arginine balance, obesity, and the age of asthma onset phenotype","volume":"187","author":"Holguin","year":"2013","journal-title":"Am. J. Respir. Crit. Care Med"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1164\/rccm.200710-1542OC","article-title":"Alterations of the arginine metabolome in asthma","volume":"178","author":"Lara","year":"2008","journal-title":"Am. J. Respir. Crit. Care Med"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1016\/0140-6736(92)90865-Z","article-title":"Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure","volume":"339","author":"Vallance","year":"1992","journal-title":"Lancet"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1038\/nrneph.2011.31","article-title":"The role of asymmetric and symmetric dimethylarginines in renal disease","volume":"7","author":"Schwedhelm","year":"2011","journal-title":"Nat. Rev. Nephrol"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1016\/j.phrs.2009.07.009","article-title":"Plasma concentrations of the cardiovascular risk factor asymmetric dimethylarginine (ADMA) are increased in patients with HIV-1 infection and correlate with immune activation markers","volume":"60","author":"Kurz","year":"2009","journal-title":"Pharmacol. Res"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1016\/j.phrs.2009.07.001","article-title":"Asymmetric dimethylarginine (ADMA) as a prospective marker of cardiovascular disease and mortality\u2014An update on patient populations with a wide range of cardiovascular risk","volume":"60","author":"Boger","year":"2009","journal-title":"Pharmacol. Res"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1164\/rccm.201204-0596PP","article-title":"Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary","volume":"187","author":"Vestbo","year":"2013","journal-title":"Am. J. Respir. Crit. Care Med"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1016\/j.jaci.2006.10.030","article-title":"Influence of cigarette smoke on the arginine pathway in asthmatic airways: Increased expression of arginase I","volume":"119","author":"Bergeron","year":"2007","journal-title":"J. Allergy Clin. Immunol"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"L489","DOI":"10.1152\/ajplung.00109.2007","article-title":"Role of nitric oxide synthase\/arginase balance in bronchial reactivity in patients with chronic obstructive pulmonary disease","volume":"294","author":"Tadie","year":"2008","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1895","DOI":"10.1016\/j.rmed.2013.08.002","article-title":"Differential effects of smoking and COPD upon circulating myeloid derived suppressor cells","volume":"107","author":"Scrimini","year":"2013","journal-title":"Respir Med"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"587","DOI":"10.2310\/JIM.0b013e31820bf475","article-title":"Increased platelet and erythrocyte arginase activity in chronic obstructive pulmonary disease associated with tobacco or wood smoke exposure","volume":"59","author":"Hicks","year":"2011","journal-title":"J. Investig. Med"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1165\/rcmb.2009-0459OC","article-title":"Cigarette smoke-induced changes to alveolar macrophage phenotype and function are improved by treatment with procysteine","volume":"44","author":"Hodge","year":"2011","journal-title":"Am. J. Respir. Cell. Mol. Biol"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Pera, T., Zuidhof, A.B., Smit, M., Menzen, M.H., Klein, T., Flik, G., Zaagsma, J., Meurs, H., and Maarsingh, H. (2014). Arginase inhibition prevents inflammation and remodeling in a guinea pig model of COPD. J. Pharmacol. Exp. Ther.","DOI":"10.1124\/jpet.113.210138"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1016\/j.jcf.2012.12.008","article-title":"A randomized controlled trial of inhaled l-arginine in patients with cystic fibrosis","volume":"12","author":"Grasemann","year":"2013","journal-title":"J. Cyst. Fibros"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Zakrzewicz, D., and Eickelberg, O. (2009). From arginine methylation to ADMA: A novel mechanism with therapeutic potential in chronic lung diseases. BMC Pulm. Med.","DOI":"10.1186\/1471-2466-9-5"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1017","DOI":"10.1016\/j.bbagen.2011.06.008","article-title":"The biochemistry of asthma","volume":"1810","author":"Gaston","year":"2011","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1016\/j.ejphar.2008.02.096","article-title":"Arginine homeostasis in allergic asthma","volume":"585","author":"Maarsingh","year":"2008","journal-title":"Eur. J. Pharmacol"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1378\/chest.12-0416","article-title":"Normal values and thresholds for the clinical interpretation of exhaled nitric oxide levels in the US general population: Results from the National Health and Nutrition Examination Survey 2007\u20132010","volume":"143","author":"See","year":"2013","journal-title":"Chest"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1164\/rccm.9120-11ST","article-title":"An official ATS clinical practice guideline: Interpretation of exhaled nitric oxide levels (FENO) for clinical applications","volume":"184","author":"Dweik","year":"2011","journal-title":"Am. J. Respir. Crit. Care Med"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"(2005). ATS\/ERS recommendations for standardized procedures for the online and offline measurement of exhaled lower respiratory nitric oxide and nasal nitric oxide, 2005. Am. J. Respir. Crit. Care Med, 171, 912\u2013930.","DOI":"10.1164\/rccm.200406-710ST"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1183\/09031936.05.00034205","article-title":"Coming together: The ATS\/ERS consensus on clinical pulmonary function testing","volume":"26","author":"Brusasco","year":"2005","journal-title":"Eur. Respir. J"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/15\/4\/6062\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T21:10:06Z","timestamp":1760217006000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/15\/4\/6062"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,4,10]]},"references-count":38,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2014,4]]}},"alternative-id":["ijms15046062"],"URL":"https:\/\/doi.org\/10.3390\/ijms15046062","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,4,10]]}}}