Statistics from Altmetric.com
Payne and co-workers describe the identification of different subgroups of paediatric asthma based on airway nitric oxide (NO) concentrations. A group of asthmatic subjects who remained symptomatic after 2 weeks of treatment with oral prednisolone included both patients who continued to have raised NO concentrations and patients with normal NO concentrations before and after prednisolone.1 Since airway NO concentrations are believed to reflect airway inflammation in asthma, the authors conclude that their findings: “ . . .suggest a different basis for symptoms between the two subgroups, with inflammation playing a less important role in those patients with normal NO levels”.
The current understanding of increased exhaled NO concentrations in asthma is based on the assumption that constitutive NO synthase (NOS) derived NO is of minor relevance and that increased exhaled NO levels reflect NO formation from activated inducible NOS (NOS2). This may, however, not be the case. We offer an alternative explanation for the interesting findings of the authors—namely, rather than being a direct reflection of airway inflammation, in at least a subgroup of patients differences in NO concentrations may result from variations in the genetic predisposition for NO synthesis. Wechsleret al 2 recently reported that exhaled NO concentrations in adult asthmatics correlate with sequence variants in the neuronal NO synthase (NOS1) gene. Furthermore, they found that NOS1 genotypes associated with high NO concentrations were significantly more frequent in asthmatic than in control subjects.2 These findings supported recent evidence that the NOS1 gene is involved in the genetics of asthma.3 4
A relation between NOS1 gene variants and airway NO concentrations also exists in cystic fibrosis (CF). In contrast to asthma, mean exhaled NO concentrations in patients with CF are significantly lower than in healthy individuals, despite the inflammatory nature of the disease. This reduction of NO is caused by different mechanisms including a lack of NOS2 expression in the CF airway epithelial cells. NO is not therefore considered to be a suitable marker of airway inflammation in CF. Interestingly, however, the same alleles in NOS1 that are related to increased NO concentrations in asthmatic subjects are also associated with higher NO concentrations in CF.5 These observations suggest that individual CF patients produce relatively high airway NO concentrations despite the absence of inducible NOS, most probably related to naturally occurring variants in the NOS1 gene. The same mechanism could explain, why individual patients with asthma have persistently high NO concentrations during treatment with steroids. Their increased airway NO levels may reflect genetically determined high constitutive NO formation and not inflammation induced NO formation.
authors' reply We thank Drs Grasemann and Ratjen for their interest in our paper1-1 and for drawing attention to an explanation for our findings which we had not considered in the discussion. As stated in the accompanying editorial,1-2there is a need for studies correlating airway histology and exhaled nitric oxide (NO) measurements. Data that we have published in abstract form,1-3 which is shortly to appear as a full paper,1-4 demonstrated in an overlapping group of patients to those we reported that those with exhaled NO concentrations of >7 ppb after a 2 week course of oral prednisolone have persistent eosinophilic airway inflammation, whereas those still symptomatic but with exhaled NO concentrations <7 ppb do not. Thus, our original conclusions are, we believe, correct, and our reported exhaled NO measurements do reflect at least two subgroups of difficult asthma—namely, an inflammatory and a non-inflammatory phenotype—rather than merely the differing genetic ability of patients to increase exhaled NO concentrations. Nonetheless, the role of polymorphisms in nitric oxide synthase genes is an important question about which more information is needed.
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.