Obesity is a comorbidity that adversely affects 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 Although obesity is associated with less asthma control, greater risk of asthma exacerbations, and reduced inhaled corticosteroid efficacy, whether in fact these conditions are causally related remains uncertain [1]. However, by defining the phenotypical aspects of this relationship, some potential new mechanistic links have been uncovered. Using cluster analyses, obesity has been shown to be an important factor among female patients whose asthma occurs after childhood and have less atopy [2, 3]. This cluster has also been associated with lower airway eosinophils and exhaled nitric oxide (eNO) [3, 4]. The inverse association between body mass index (BMI) and eNO [5] may be explained by an imbalance between L-arginine and one of its methylated products known as asymmetric dimethyl arginine (ADMA) [6, 7]. L-arginine is the substrate that nitric oxide synthase (NOS) uses to generate NO. However, L-arginine is methylated to ADMA, which is an endogenous inhibitor of all NOS isoforms [8]. In addition, ADMA can uncouple NOS and preferentially generate anion superoxide instead of NO [9]. Therefore, conditions favoring a lower L-arginine/ADMA balance would in theory contribute to reducing NO airway bioavailability and increasing airway oxidative stress. This phenomenon has been more extensively studied in the vasculature, as a mechanism leading to endothelial dysfunction or impaired NO-mediated vasodilatation [10]. However, in the lung, the L-arginine/ADMA balance is just beginning to surface as a potential explanation to understand metabolic diseases such
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