Alterations of the Arginine Metabolome in Asthma

Abstract

Rationale: As the sole nitrogen donor in nitric oxide (NO) synthesis and key intermediate in the urea cycle, arginine and its metabolic pathways are integrally linked to cellular respiration, metabolism, and inflammation. Objectives: We hypothesized that arginine (Arg) bioavailability would be associated with airflow abnormalities and inflammation in subjects with asthma, and would be informative for asthma severity. Methods: Arg bioavailability was assessed in subjects with severe and nonsevere asthma and healthy control subjects by determination of plasma Arg relative to its metabolic products, ornithine and citrulline, and relative to methylarginine inhibitors of NO synthases, and by serum arginase activity. Inflammatory parameters, including fraction of exhaled NO (FE NO ), IgE, skin test positivity to allergens, bronchoalveolar lavage, and blood eosinophils, were also evaluated. Measurements and Main Results: Subjects with asthma had greater Arg bioavailability, but also increased Arg catabolism compared with healthy control subjects, as evidenced by higher levels of FE NO and serum arginase activity. However, Arg bioavailability was positively associated with FE NO only in healthy control subjects; Arg bioavailability was unrelated to FE NO or other inflammatory parameters in severe or nonsevere asthma. Inflammatory parameters were related to airflow obstruction and reactivity in nonsevere asthma, but not in severe asthma. Conversely, Arg bioavailability was related to airflow obstruction in severe asthma, but not in nonsevere asthma. Modeling confirmed that measures of Arg bioavailabilty predict airflow obstruction only in severe asthma. Conclusions: Unlike FE NO , Arg bioavailability is not a surrogate measure of inflammation; however, Arg bioavailability is strongly associated with airflow abnormalities in severe asthma.

Asymmetric dimethylarginine and asthma

“…This argument is consistent with the findings of HOLGUIN et al [4], who reported that ADMA levels in peripheral plasma samples from patients with severe, late-onset asthma correlated with worsening of the FEV1 % pred, FVC % pred and symptom scores. These data and data from adults with severe asthma [5] suggest that changes in circulating ADMA are associated with specific well-defined phenotypic characteristics that may not manifest with milder disease phenotypes.…”

Anti-malarial drug artesunate restores metabolic changes in experimental allergic asthma

“…Ornithine is converted to proline and then to valine (Weeda et al 1980). Proline is associated with increased collagen formation (Barbul 2008;Lara et al 2008), while valine is linked to tissue repair (Smith and Sun 1995). These findings suggest that artesunate and dexamethasone could limit arginine-proline metabolism in asthma (Fig.…”

“…proline, valine, homoserine and alanine), but reversed the drop in glucose, mannose, galactose, arabinose and galacturonic acid in asthma. The arginine-proline pathway is implicated in asthma (Meurs et al 2002;Lara et al 2008), whereby increase in arginase activity can lead to augmented conversion of L-arginine to urea and ornithine. Ornithine is converted to proline and then to valine (Weeda et al 1980).…”

“…Metabolomics refers to the global investigation of metabolites in biological systems (comparing normal to disease) (Xu et al 2014), and has been applied to allergic asthma to profile metabolic changes and identify disease biomarkers (Lara et al 2008;Ho et al 2013Ho et al , 2014bSaude et al 2009Saude et al , 2011Mattarucchi et al 2012;Jung et al 2013). We have recently uncovered novel disease-relevant metabolic changes in the bronchoalveolar lavage fluid (BALF) from experimental mouse asthma, which involved major losses of sugars with resultant increases in energy metabolites and reductions of sterols (Ho et al , 2014b.…”

DNA Methylation in the Arginase–Nitric Oxide Synthase Pathway Is Associated with Exhaled Nitric Oxide in Children with Asthma

“…However, whether low arginine bioavailability predicts FeNO levels is uncertain, because at least two studies have shown no association or paradoxically increased FeNO levels in individuals with asthma (41,42). Not all levels of ARG expression result in inhibition of NO production and stimuli can both induce ARG and inhibit iNOS expression, making prediction of downstream consequences difficult (43).…”