Abstract
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.
Highlights
L-Arginine metabolism plays an important role in the maintenance of airways tone and function by production of nitric oxide (NO) and L-citrulline, via the NO synthase (NOS) pathway, as well asL-ornithine and the polyamines, via arginase and ornithine decarboxylase, respectively (Figure 1) [1,2].Dysregulation of the competing enzymes has been shown to contribute to airway obstruction in asthma and in patients with cystic fibrosis [3,4,5]
The direct and significant correlation between sputum L-ornithine and asymmetric dimethylarginine (ADMA) levels, which would appear to be due to two independent pathways suggests that higher concentrations of the endogenous NOS inhibitor ADMA result in increased availability of L-arginine for the arginase pathway and subsequently leads to the increased formation of L-ornithine
Our preliminary analysis demonstrates the presence of the competitive NOS inhibitor ADMA
Summary
L-Arginine metabolism plays an important role in the maintenance of airways tone and function by production of nitric oxide (NO) and L-citrulline, via the NO synthase (NOS) pathway, as well as. Recent evidence suggests that arginase controls NOS activity in airways through limitation of L-arginine bioavailability, and by producing L-ornithine, the precursor of polyamine biosynthesis [15,16]. The shift of L-arginine metabolism toward the arginase pathway has been suggested to contribute to remodeling of asthma airways, due to the production of polyamines [12,16]. NOS activity can be reduced by the accumulation of endogenous inhibitors such as ADMA, a product of protein degradation that has only recently been recognized as being associated with lung disease [3,4,5,18,19]. During proteolysis, which act as endogenous inhibitors of NOS, as well as symmetric dimethylarginine (SDMA), which competes with L-arginine for uptake by the cationic amino acid transporter-2 [1]
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