Asymmetric dimethylarginine and asthma

To the Editor:

With interest we have read the letter by Lau et al. [1] regarding circulating asymmetric dimethylarginine (ADMA) in a cohort of children with asthma from the Australian Childhood Asthma Prevention Study.

ADMA, a product of protein degradation, is an endogenous nitric oxide synthase inhibitor that has been shown to be increased in mouse models of allergic airway inflammation and to be associated with airways hyperresponsiveness in these animals [2]. ADMA has also been reported to be increased in sputum samples [2] and exhaled breath condensates [3] from paediatric patients with asthma. Increased ADMA in serum has recently been found to be associated with the severity of symptoms in late-onset asthma and obesity [4].

Lau et al. [1] found no difference in serum ADMA between clinically stable children with or without wheezing in the previous 12 months in their cohort of 8-year-old children. However, there was also no difference in post-bronchodilator spirometry (forced vital capacity (FVC) or the per cent predicted (% pred) forced expiratory volume in 1 s (FEV₁) or FEV₁/FVC) between the groups, nor was there evidence for increased exhaled nitric oxide fraction (F_eNO) in current asthma, as the mean F_eNO, although statistically different, was well within the normal range and very similar between the groups (mean±sd 8.9±9.3 versus 11.1±7.7 ppb). Serum ADMA did not correlate with the (log-transformed) F_eNO.

One explanation for the discrepancy between their results and previous reports could be that markers of l-arginine/nitric oxide homeostasis in airways may not be altered in the blood of stable patients with mild asthma and normal pulmonary function. 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.

We would like to provide additional supporting evidence of the potential role of ADMA in airway responsiveness: we obtained induced-sputum samples from 10 adult subjects with mild, eosinophilic asthma (five males, five females; median age 36 years, range 18–61 years; normal baseline FEV₁ of 100.4±4.7% pred) at baseline and 7 and 24 hours following a controlled inhaled allergen challenge, as previously described [6, 7]. Baseline sputum eosinophils (1.6±0.9%) increased to 7.6±3.1% and 12.5±6.0% at 7 and 24 hours following allergen challenge, respectively (p<0.05 by Friedman test). Neutrophil counts in sputum were 39.0±6.4% (maximum 69%) at baseline. Changes in pulmonary function testing consistent with airways hyperresponsiveness and airflow limitation (i.e. reduction in the provocative concentration causing a 20% fall in FEV₁ (PC₂₀), and decline in FEV₁ % pred) were observed in these subjects, along with a significant increase in sputum ADMA after challenge (p<0.05 by repeated measures ANOVA) (fig. 1). Thus, in these adult subjects with mild allergic asthma, concentrations of the nitric oxide synthase inhibitor ADMA increase significantly in sputum after allergen challenge, concomitant with the onset of airways obstruction. These data suggest that ADMA is involved in the asthmatic response and that changes in ADMA in the airways occur in acute exacerbations. It will be very interesting to see what future studies comparing the utility of biomarkers between different compartments will tell us about the role of ADMA in asthma.

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Figure 1–

a) Methacholine provocative concentration causing a 20% fall in forced expiratory volume in 1 s (PC₂₀) is reduced in asthmatic subjects 24 h after specific allergen challenge. b) Forced expiratory volume in 1 s (FEV₁) % predicted is similarly attenuated at 24 h after allergen challenge, compared with the baseline (pre-challenge). c) A significant increase in sputum asymmetric dimethylarginine (ADMA) concentration is observed at 7 and 24 h after allergen challenge. n=8 in each group. *: p<0.05; **: p<0.01.

• Received May 8, 2013.
• Accepted May 17, 2013.

• ©ERS 2014