Abstract
BackgroundContribution of nitric-oxide (NO) pathway to the pathogenesis of bronchial asthma (asthma) is ambiguous as NO may confer both protective and detrimental effects depending on the NO synthase (NOS) isoforms, tissue compartments and underlying pathological conditions (e.g. systemic inflammation). Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor and uncoupler of NOS with distinct selectivity for NOS isoforms. In a cross-sectional study, we assessed whether ADMA is an independent predictor of airway resistance (Raw) in therapy-controlled asthma.Methods154 therapy-controlled asthma patients were recruited. ADMA, symmetric dimethylarginine and arginine were quantitated by HPLC with fluorescent detection. Pulmonary function test was done using whole-body plethysmography, quality of life via St. George’s Respiratory questionnaire (SGRQ). Multiple linear regression was used to identify independent determinants of Raw. The final model was stratified based on therapy control.ResultsEvidence for systemic inflammation indicated by CRP and procalcitonin was lacking in our sample. Log Raw showed significant positive correlation with log ADMA in the whole data set and well-controlled but not in the not well-controlled stratum (Spearman correlation coefficients: 0.27, p < 0.001; 0.30, p < 0.001; 0.12, p = 0.51 respectively). This relationship remained significant after adjusting for confounders by multiple linear regression (β = 0.22, CI 0.054, 0.383 p = 0.01). FEF 25–75% % predicted and SGRQ Total score showed significant negative while SGRQ Activity score showed significant positive correlation with Raw in the final model.ConclusionsPositive correlation between Raw and ADMA in the absence of systemic inflammation implies that higher ADMA has detrimental effect on NO homeostasis and can contribute to a poor outcome in asthma.
Highlights
Contribution of nitric-oxide (NO) pathway to the pathogenesis of bronchial asthma is ambiguous as NO may confer both protective and detrimental effects depending on the NO synthase (NOS) isoforms, tissue compartments and underlying pathological conditions
Defined daily dose of inhaled corticosteroids was determined to allow comparisons across treatment regimens [27]. airway resistance (Raw) is reflective of changes in alveolar pressure over changes in flow as it is highly dependent on state of airways, it is an appropriate parameter for quantifying airflow limitation [28]
Patients The treatment history of the 154 asthma patients included in our study were as follows: 4 patients were treatment naïve at the time of inclusion; 3 patients received a fixed combination of ipratropium with fenoterol; 45 patients were treated with short-acting beta agonists (43 of them with an inhaled corticosteroid); 146 patients received inhaled corticosteroid as a mono-component preparation (n = 18) or in fixed combination with long-acting and/ or short-acting beta agonists (n = 128)
Summary
Contribution of nitric-oxide (NO) pathway to the pathogenesis of bronchial asthma (asthma) is ambiguous as NO may confer both protective and detrimental effects depending on the NO synthase (NOS) isoforms, tissue compartments and underlying pathological conditions (e.g. systemic inflammation). The third isoform is the inducible NOS (iNOS) that, albeit continuously expressed in lung epithelial cells [10], is present upon its induction by pro-inflammatory cytokines. These latter molecules activate the nuclear transcription factor NF-κB that leads to iNOS expression and thereby sustained high release of NO (in nanomolar concentration) over the course of hours to days [8]. L-arginine or tetrahydrobiopterin depletion may cause uncoupling of all three NOS isoforms, switching the enzyme’s function to produce superoxide instead of NO [11, 17, 18]
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