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Hindawi Publishing Corporation Journal of Allergy Volume 2013, Article ID 714595, 5 pages http://dx.doi.org/10.1155/2013/714595 Review Article Arginine and Nitric Oxide Pathways in Obesity-Associated Asthma Fernando Holguin Division of Pulmonary, Allergy & Critical Care, Asthma Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA Correspondence should be addressed to Fernando Holguin; firstname.lastname@example.org Received 20 February 2013; Accepted 2 April 2013 Academic Editor: Allan Linneberg Copyright © 2013 Fernando Holguin. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Obesity is a comorbidity that adversely aeff cts asthma severity and control by mechanisms that are not fully understood. This review will discuss evidence supporting a role for nitric oxide (NO) as a potential mechanistic link between obesity and late-onset asthma (>12 years). Several studies have shown that there is an inverse association between increasing body mass index (BMI) and reduced exhaled NO. Newer evidence suggests that a potential explanation for this paradoxical relationship is related to nitric oxide synthase (NOS) uncoupling, which occurs due to an imbalance between L-arginine (NOS substrate) and its endogenous inhibitor, asymmetric di-methyl arginine (ADMA). The review will propose a theoretical framework to understand the relevance of this pathway and how it may differ between early and late-onset obese asthmatics. Finally, the paper will discuss potential new therapeutic approaches, based on these paradigms, for improving the respiratory health of obese subjects with asthma. 1. Introduction This phenomenon has been more extensively studied in the vasculature, as a mechanism leading to endothelial dysfunc- Although obesity is associated with less asthma control, tion or impaired NO-mediated vasodilatation . However, greater risk of asthma exacerbations, and reduced inhaled in the lung, the L-arginine/ADMA balance is just beginning corticosteroid efficacy, whether in fact these conditions are to surface as a potential explanation to understand metabolic causally related remains uncertain . However, by den fi ing diseases such as obesity and how these conditions can aeff ct the phenotypical aspects of this relationship, some potential airway function. This review will discuss the role of L- new mechanistic links have been uncovered. Using cluster arginine, arginases, and ADMA on airway NO metabolism analyses, obesity has been shown to be an important factor in relation to obesity and propose a theoretical framework, among female patients whose asthma occurs aeft r childhood by which an L-arginine/ADMA imbalance in obesity may andhavelessatopy [2, 3]. Thiscluster hasalsobeenassociated explain why obesity leads to worsened respiratory symptoms with lower airway eosinophils and exhaled nitric oxide (eNO) in some asthmatics. [3, 4]. eTh inverse association between body mass index (BMI) and eNO  may be explained by an imbalance 2. Exhaled Nitric Oxide and between L-arginine and one of its methylated products known as asymmetric dimethyl arginine (ADMA) [6, 7]. L- Arginine Metabolism; Implications to arginine is the substrate that nitric oxide synthase (NOS) Obesity and Asthma uses to generate NO. However, L-arginine is methylated to ADMA, which is an endogenous inhibitor of all NOS Historically, eNO has been studied as a biomarker of isoforms . In addition, ADMA can uncouple NOS and eosinophilic airway inflammation and as a potential preferentially generate anion superoxide instead of NO . biomarker to monitor response to inhaled corticosteroids. eTh refore, conditions favoring a lower L-arginine/ADMA Given that high eNO levels track with asthma exacerbations balance would in theory contribute to reducing NO air- andpoorcontrol,itisbelievedthatincreased NO could way bioavailability and increasing airway oxidative stress. potentiallyhaveacausativeroleinasthmaseverity, and 2 Journal of Allergy indeed, this may be the case, if one considers the NO resistance was attributed to reduced NO bioavailability, while canleadtothe formationofmorereactivenitrogen the reduced compliance was linked to increased collagen species (RNS) in the setting of airway oxidative stress . deposition. Interestingly, these ndin fi gs occurred in the However, it is unknown whether elevated NO levels per absence of increases in traditional biomarkers of allergic se have any causative role in worsening asthma severity. airway inflammation [ 28]. In fact, NO inhibition lacks clinical benefits in humans, Evidence that ADMA is associated with reduced eNO and NO inhalation has been reported to prevent, not in humans is supported by one study showing that sputum to induce, bronchial hyperresponsiveness [12–15]. These ADMA and the L-arginine/ADMA ratio are associated with results may be explained on the basis that NO, which eNO (𝑟 = −0.5319 and 0.500, resp., both 𝑃 < 0.05 )in is constitutively produced by the airway epithelium, adults and children; in addition, sputum ADMA levels were contributes to maintaining adequate airway function; higher in asthmatics versus controls . Plasma ADMA and for example, NO has been implicated in ciliary beating, the L-arginine/ADMA ratio have been found to have similar maintaining bronchodilation through the formation of associations with eNO among late onset asthmatics partic- s-nitrosothiol compounds, and in bactericidal functions ipating in the Severe Asthma Research Program (SARP) [16, 17]. Also, reduced eNO is associated with several chronic study ; however, whether increased airway or plasma lung diseases [18–20]. eTh refore, having reduced eNO in ADMA levels have any impact on the respiratory systems is obesity, far from being beneficial, may indicate a major uncertain. Murine OVA models show that pretreatment with detrimental derangement of NO metabolism . ADMA enhances allergic airway inflammation, bronchial Reduced NO bioavailability in obesity and asthma could hyperresponsiveness, and airway remodeling [9, 28]. These be potentially explained by several mechanisms, including (a) experiments would suggest that increased ADMA plays a reducedNOS substrate(L-arginine), (b)endogenousNOS role during acute allergic inflammation; yet, the SARP study inhibition, (c) combination of (a) and (b), and (d) increased suggests that reductions in plasma L-arginine/ADMA are consumption of airway NO into other RNS. Increased associated with reduced FEV , quality of life, and more arginase expression may reduce L-arginine bioavailability. frequent respiratory symptoms. Based on these results, it Arginases are intracellular catabolic enzymes that metabolize could be theorized that lower L-arginine/ADMA balance arginine into ornithine and urea and have been shown to and its effects on airway NO bioavailability could not only be higher among patients with asthma . Compared to enhance airway inflammation during acute exacerbations but healthy controls, subjects with asthma have been found to also affect airway function more chronically. have reduced plasma arginine levels and increased arginase Another mechanism potentially contributing to reduced activity, which have been associated with reduced FEV eNO in obesity is airway oxidative stress, which can lead to and greater airway obstruction . Whether obesity could the formation of RNS and therefore lower the NO fraction potentially exacerbate this phenomenon is unknown; how- that is actually measured . Compared to healthy controls, ever, the fact that increased BMI has been associated with subjects with asthma have greater concentration of airway increased arginase expression suggests that this might be oxidative stress biomarkers, which appear to increase in possible . relation to BMI [5, 31, 32]. While this has been demon- ADMA is one of three methylated analogs of L-arginine strated in exhaled breath condensates and bronchoalveolar occurring through posttranslational modicfi ation; however, lavage, an interaction between asthma and obesity has not ADMA is the only one that can competitively inhibit all nitric been observed in a larger study population using plasma oxide synthase (NOS) isoforms. ADMA is synthesized from F2-isoprostanes as biomarkers of systemic oxidative stress L-arginine by protein-arginine methyltransferases (PRMTs) . It is therefore possible that in subjects with asthma, and degraded into mono- or dimethylamine and citrulline by obesity increases airway and not systemic oxidative stress. dimethylarginine dimethylaminohydrolase (DDAH). Condi- The sources for increased airway oxidative stress in relation tions such as obesity, metabolic syndrome, and diabetes have to BMI are unknown and seem to be (at least at baseline) been associated with increased PRMT activity and/or reduc- independent of the number of inflammatory cells present in tion in DDAH function. eTh combination of these enzymatic the airway. Two potential sources may involve a lower L- changes could potentially explain why obesity in asthma arginine/ADMA balance leading to the preferential forma- contributes to higher ADMA levels [25, 26]. Citrulline can tion of anion superoxide from epithelial NOS and increased be subsequently recycled into L-arginine . By competing airway leptin levels, which have been associated with greater with L-arginine, ADMA uncouples NOS causing electrons airway levels of proinflammatory cytokines [ 34]. flowing from theNADPH reductasedomaintothe oxyge- nase domain to be diverted into molecular oxygen rather 3. Arginine and Nitric Oxide than to L-arginine . Under uncoupling conditions, NOS generates superoxide, which correlates with airway oxidative Metabolism in Obesity and Asthma, stress in murine OVA models . In stimulated murine Unique to a Phenotype? airway epithelial cells, administration of ADMA reduces nitrite production while increasing superoxide levels in a Recent studies have confirmed that asthma is not a single dose-dependent manner . Continuous ADMA infusion disease but rather a heterogeneous group of clinical entities for 2 weeks also increased airway resistance and reduced with different risk factors, varying response to therapies, lung compliance in vivo in mice. This increased airway degree of lung function impairment, and healthcare use, to Journal of Allergy 3 Early onset asthma phenotype Late onset asthma phenotype L-arginine Asthma Obesity Arginase activity Asthma ADMA Metabolic syndrome Obesity NOS inhibition and uncoupling Reduced airway NO bioavailability Increased airway oxidative stress Increased respiratory Disease severity symptoms (wheezing, primarily driven by tightness, dyspnea) “Airway dysfunction syndrome” allergic airway inflammation (resistant to steroids?) Obesity in many cases may be the result rather than cause of asthma severity? Figure 1: Theoretical framework for the interaction of L-arginine-ADMA and NO in obesity and asthma. Among subjects with late onset (>12 years of age) asthma, reduced L-arginine/ADMA ratios uncouple airway NOS, leading to greater airway oxidative stress and reduced NO bioavailability. In turn, this impairs bronchodilation, worsening wheezing, dyspnea, and chest tightness. Several factors may contribute to having lower L-arginine/ADMA. Obesity and asthma both have been associated with decreased L-arginine bioavailability and increased L-arginine catabolism. Also, obesity has been associated with increased ADMA levels independently from asthma. This algorithm may not be present in those with early onset asthma (<12 years), either because obesity and asthma induce different eeff cts on the L-arginine-ADMA metabolic pathway depending on the age of asthma onset or because other mechanistic pathways drive severity and changes in airway NO metabolism in the early onset asthmatics. name a few . While every asthma phenotype has the phenotype. Alternatively, obesity induces similar changes in potential of being obese, the relationship between obesity both groups; however, in the early onset phenotype other and asthma may differ. For example, obesity seems to be mechanisms (i.e., eosinophilic inflammation, atopy) drive mostly associated with subjects whose asthma occurs after asthma severity and override any effects resulting from the childhoodandhavelessatopy.Thisphenotypeshowsahigher obesity—mediated changes in L-arginine—NO metabolism degree of healthcare utilization, with mild lung function (see Figure 1). impairment and lower eNO [2, 3]. Results from these cluster analyses lead us to hypothesize that the L-arginine/ADMA balance and its relation to NO would differ between the ages 4. Treatment Options of onset asthma phenotypes. Indeed, there were remarkable differences between subjects with childhood ( <12 years) If L-arginine/ADMA is indeed one of the mechanistic path- versus later (≥12 years) onset asthma. Among later onset ways by which obesity aeff cts asthma, this could open the asthmatics only, the inverse association between eNO and door to new therapeutic options. L-arginine can eeff ctively BMI was partly explained by the L-arginine/ADMA ratio; overcome the effects of ADMA on NOS and thus could also, in this phenotype, lower L-arginine/ADMA ratios were become an additional treatment for obese late onset asthmat- associated with poorer asthma-related quality of life, reduced ics, particularly forthose that have lowerornormaleNO and FEV , and more frequent respiratory symptoms, such as are not highly eosinophilic. Supplementation with L-arginine wheezing, dyspnea, and chest tightness . Interestingly, hasbeenshown to increase eNOinchildrenand adults there were no associations with cough, sputum production, and to reduce airway inflammation and bronchial hyper- or increased healthcare utilization. Although this is a cross- responsiveness in murine ovalbumin sensitization models sectional study and causation cannot be established, it could [36–39]. In addition, L-arginine supplementation can prevent be speculated that in this later onset phenotype, lower L- NOS uncoupling . Unfortunately, its use as a therapeutic arginine/ADMA leads to reduced airway NO bioavailability, modality is limited, given its extensive first pass metabolism whichinturncausesan“airwaydysfunctionsyndrome,”char- in theliver andintestine . This is perhaps why one study acterized primarily by impaired bronchial dilation without found only modest improvements in FEV in asthmatics aer ft increased sputum production or cough. 1 week of L-arginine supplementation . Also, because Why there are differences in L-arginine and NO L-arginine catabolism by arginase generates ornithine, a metabolism across age of asthma onset phenotypes is precursor to proline and polyamine, supplementation with L- unknown. 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