Asymmetric Dimethylarginine

Abstract

Nitric oxide (NO) is a messenger molecule that is critical for the maintenance of normal lung and airway function. NO is the product of the enzymatic conversion of l-arginine to l-citrulline, which is catalyzed by NO synthases (NOSs). The regulation of NOS activity depends on transcriptional and posttranscriptional mechanisms and varies among the different NOS isoforms. Increased expression of inducible NOS in airway inflammation is thought to cause the elevated exhaled NO levels that can be found in patients with asthma.1Barnes PJ Dweik RA Gelb AF et al.Exhaled nitric oxide in pulmonary diseases: a comprehensive review.Chest. 2010; 138: 682-692Abstract Full Text Full Text PDF PubMed Scopus (313) Google Scholar However, recent evidence from animal models suggests that airway hyperresponsiveness in asthma may actually be related to reduced bioavailability of l-arginine for NOS and subsequent NO deficiency. One of the mechanisms resulting in decreased l-arginine bioavailability in asthma is the increased expression and activity of arginase, an enzyme that competes with NOS for l-arginine as substrate.2Maarsingh H Zaagsma J Meurs H Arginase: a key enzyme in the pathophysiology of allergic asthma opening novel therapeutic perspectives.Br J Pharmacol. 2009; 158: 652-664Crossref PubMed Scopus (110) Google Scholar, 3North ML Khanna N Marsden PA Grasemann H Scott JA Functionally important role for arginase 1 in the airway hyperresponsiveness of asthma.Am J Physiol Lung Cell Mol Physiol. 2009; 296: L911-L920Crossref PubMed Scopus (111) Google Scholar, 4North ML Meurs H Zaagsma J Scott JA Maarsingh H Arginase in asthma–recent developments in animal and human studies.The Open Nitric Oxide Journal. 2010; 2: 20-36Crossref Google Scholar Downstream products of arginase activity include proline, a precursor for collagen formation, and the l-ornithine-derived polyamines. The polyamine spermine acts as an inhibitor of NOS and recently has been identified as being increased in human asthma and contributing significantly to impaired airway function in a mouse model of asthma.5North ML, Grasemann H, Khanna N, Inman MD, Gauvreau GM, Scott JA. Increased ornithine-derived polyamines cause airways hyperresponsiveness in asthma [published online ahead of print March 7, 2013]. Am J Respir Cell Mol Biol. doi: 10.1165/rcmb.2012-0323OC.Google Scholar Another endogenous inhibitor of NOS is asymmetric dimethylarginine (ADMA), which is a product of protein degradation. ADMA was previously found to be present and increased in sputum of pediatric patients with asthma.6Scott JA North ML Rafii M et al.Asymmetric dimethylarginine is increased in asthma.Am J Respir Crit Care Med. 2011; 184: 779-785Crossref PubMed Scopus (75) Google Scholar Thus, NO production in asthma airways may be reduced by both increased arginase activity, which leads to substrate limitation for NOS and production of polyamines, and by increased ADMA, which inhibits NOS. In support of the animal studies that suggested an important role for abnormalities in the l-arginine metabolism for asthma, systemic arginine bioavailability was reduced in asthma exacerbation7Morris CR Poljakovic M Lavrisha L Machado L Kuypers FA Morris Jr, SM Decreased arginine bioavailability and increased serum arginase activity in asthma.Am J Respir Crit Care Med. 2004; 170: 148-153Crossref PubMed Google Scholar and was strongly associated with airflow abnormalities in patients with severe asthma.8Lara A Khatri SB Wang Z National Heart, Lung, and Blood Institute's Severe Asthma Research Program et al.Alterations of the arginine metabolome in asthma.Am J Respir Crit Care Med. 2008; 178: 673-681Crossref PubMed Scopus (102) Google Scholar Furthermore, decreased l-arginine/ADMA plasma ratios were associated with reduced lung function and increased frequency of respiratory symptoms in a recent study of obese children with late-onset asthma.9Holguin F Comhair SA Hazen SL et al.An association between (L)-arginine/asymmetric dimethyl arginine balance, obesity, and the age of asthma onset phenotype.Am J Respir Crit Care Med. 2013; 187: 153-159Crossref PubMed Scopus (117) Google Scholar In their article published in this issue of CHEST (see page 405), Carraro and colleagues10Carraro S Giordano G Piacentini G et al.Asymmetric dimethylarginine in exhaled breath condensate and serum of children with asthma.Chest. 2013; 144: 405-410Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar measured ADMA in exhaled breath condensate (EBC) from children with asthma and from healthy control subjects. Using this noninvasive technique, their findings confirmed that ADMA is increased in the airways of patients with asthma.10Carraro S Giordano G Piacentini G et al.Asymmetric dimethylarginine in exhaled breath condensate and serum of children with asthma.Chest. 2013; 144: 405-410Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar Their observation that ADMA could be found in most EBC samples is encouraging, as the collection of EBC can be performed in all age groups, including younger children unable to produce sputum, and can be performed before children are capable of undergoing standard pulmonary function testing.11Corradi M Zinelli C Caffarelli C Exhaled breath biomarkers in asthmatic children.Inflamm Allergy Drug Targets. 2007; 6: 150-159Crossref PubMed Scopus (29) Google Scholar Interestingly, although increased ADMA, as it inhibits NOS, should result in decreased NO formation and airway obstruction, Carraro and colleagues10Carraro S Giordano G Piacentini G et al.Asymmetric dimethylarginine in exhaled breath condensate and serum of children with asthma.Chest. 2013; 144: 405-410Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar failed to find significant correlations between EBC ADMA/tyrosine levels and exhaled NO or measures of airway obstruction on spirometry. There was also no significant correlation between ADMA/tyrosine levels in EBC and ADMA in serum. The lack of correlations may be explained, in part, by characteristics of the study population that included a wide range in age of patients (5-17 years), diversity in asthma severity and pulmonary function test results (z-score 95% CI, −0.44 to 0.06 for FEV1 and −0.79 to 0.30 for forced expiratory flow at 25%-75%), and the use of medications (40% on long-acting β agonists, 75% on inhaled corticosteroids [200-800 μg daily budesonide or equivalent]).10Carraro S Giordano G Piacentini G et al.Asymmetric dimethylarginine in exhaled breath condensate and serum of children with asthma.Chest. 2013; 144: 405-410Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar More information is needed before it can be concluded that ADMA in EBC can serve as a new diagnostic tool in asthma. It must be demonstrated that ADMA in EBC accurately reflects ADMA levels in the airways. A comparison of EBC with sputum and/or plasma concentrations would help address this. Questions of repeatability and accuracy of the methods used need to be addressed as well. Also, the biologic stability of ADMA and the l-arginine metabolites in airway fluid represent unknown variables in the interpretation of these findings. Quantification of a single molecule may not adequately reflect the complex l-arginine metabolism. Using liquid chromatography-tandem mass spectrometry, it should be possible to measure, in addition to ADMA, other metabolites, including l-arginine and l-ornithine, to provide a measure of l-arginine bioavailability (l-arginine:l-ornithine), as well as some indication of NOS functional impairment, such as the l-arginine:ADMA ratio or concentrations of the l-arginine-derived polyamine spermine. A more comprehensive EBC analysis could also include an inflammatory profile and markers of oxidative stress such as peroxynitrite, which would also be reflective of dysfunction in NOS metabolism (ie, NOS uncoupling). With this type of profiling, it might be possible to distinguish subgroups of asthma phenotypes, gain new knowledge on underlying mechanisms, and identify markers of disease that could prove useful for follow-up of disease severity and response to therapeutic interventions. In summary, what we can learn from this study is that the NOS inhibitor ADMA can be measured in EBC obtained from children with asthma and that this marker is increased in children with asthma compared with control subjects. Future studies in patients with well-defined asthma phenotypes are needed to evaluate the diagnostic potential of l-arginine metabolites including ADMA and to relate such changes to functional outcomes.