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Exhaled nitric oxide in COPD: glancing through a smoke screen
  1. P J STERK,
  2. H W F M DE GOUW,
  4. K F RABE
  1. Department of Pulmonology
  2. Leiden University Medical Center
  3. P O Box 9600
  4. NL-2300 RC Leiden
  5. The Netherlands
  1. Professor P J Sterk.

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There is worldwide increasing awareness of the human and socioeconomic impact of chronic obstructive pulmonary disease (COPD) which is a major cause of morbidity and mortality.1 Even though its pathogenesis in industrialised countries is linked to a well known cause—namely, tobacco smoking—it is not envisaged that this knowledge will lead to breakthroughs in the prevention of this disease during the years to come. Hence, current efforts are mainly directed towards improving the diagnosis and management of patients with COPD.1

During the past decade it has been recognised that the pathophysiology of COPD includes (multiple) inflammatory pathways within the airways and lung parenchyma. Apart from the emphysematous lesions, smokers with chronic airflow limitation usually have increased submucosal glands, some degree of epithelial shedding, and an increase in the amount of airway smooth muscle.2 However, the most important pathological changes are found within the small airways where the inflammation is characterised by increased numbers of macrophages, mast cells,3 neutrophils, and CD8+ T cells,4together with increased expression of growth factors such as transforming growth factor β (TGF-β).5 Most of these abnormalities can be detected in bronchial biopsy specimens from the large airways6 and are related to the severity of airflow limitation.7

It is not therefore unexpected that attempts have been made to detect and monitor such inflammatory changes in COPD by non-invasive techniques. The first valuable step has been made by using the measurement of airway hyperresponsiveness to methacholine8which, indeed, provides complementary information to symptoms and lung function on the course and prognosis of the disease. More recent efforts concentrate on cellular or soluble markers of inflammation in induced sputum9 or molecular markers in exhaled air.10 11 Is there a need to monitor inflammatory activity in COPD and, if so, is the easiest method—measuring exhaled nitric oxide (NO)—an appropriate one to do so?

Is exhaled NO increased in COPD?

The current issue of Thorax includes two recent studies on the validity of exhaled NO measurements in the detection of COPD among (ex-)smoking subjects. Their partially contradictory findings illustrate the complexity of applying and interpreting such a molecular marker in a heterogenous disease entity such as COPD. Corradi et al 12 compared levels of exhaled NO in smoking and non-smoking healthy subjects with smoking and ex-smoking, non-atopic, steroid naive patients with COPD in a cross sectional design. They observed that the presence of clinically stable COPD was associated with increased levels of exhaled NO compared with healthy controls, whilst current smoking was accompanied by reduced levels of exhaled NO compared with non-smokers or ex-smokers in both groups. Remarkably, exhaled NO levels decreased with the number of pack years and with the degree of airflow limitation.12 This suggests that exhaled NO can be a marker of COPD, particularly in ex-smoking patients with a relatively short smoking history. These findings could not be confirmed in the second study in this issue by Rutgers et al 13 who did not observe differences in the excretion rate of NO in exhaled air between non-atopic, steroid naive patients with COPD and healthy controls, whilst the reduction of exhaled NO levels by current smoking was seen only in the healthy subjects. The lack of differences between COPD and healthy controls was confirmed when using nitrite/nitrate measurements in sputum supernatant and the expression of inducible NO synthase (iNOS) in sputum macrophages. However, exhaled NO appeared to be positively correlated with the percentage of eosinophils in induced sputum, which indicates that exhaled NO might specifically reflect a certain phenotype of COPD.13

Is this a controversy?

When taking previously published reports14 15 into account there appears to be controversy and confusion with regard to exhaled NO in clinically stable COPD. This is even more apparent since the authors of the two largely opposing articles in this issue claim to confirm the previous findings on the same topic by Maziaket al.15 What are the explanations for the present contradictory findings? Firstly, there are obvious differences in methodology between the available studies which are extremely hard to interpret. This refers to the comparison of, for example, single breath12 versus tidal breathing method,13 16 exhaled NO concentrations (ppb)12 versus the excretion rate (nmol/min),13 or differences in expiratory flow rates.12 13 This underlines the need for rigorous standardisation, and attempts have recently been made to achieve this.11 17 Secondly, the patients in the study by Corradiet al 12 had more severe degrees of airflow limitation than those in the study of Rutgerset al 13 and, in addition, at given values of FEV1 may have had a different balance between the involvement of airways and parenchymal disease. Taken together, the currently available data may not be regarded as being controversial but merely incomparable. This implies that, at this stage, measurements of exhaled NO cannot generally be recommended in the detection of clinically stable COPD.

Can we skip exhaled NO in COPD?

Is this the end of measuring exhaled NO in COPD? Perhaps. One might question the rationale for measuring inflammatory activity by exhaled NO during clinically stable conditions of a chronic disease in which parenchymal destruction and airway remodelling predominate in causing airflow limitation.18 On the other hand, there is convincing evidence that exacerbations of the disease are associated with increases in exhaled NO15 which might be associated with eosinophilic inflammation.19 Indeed, the latter might be detected by measurements of exhaled NO13 and seems to reflect the potential benefits of oral20 or inhaled21 steroid treatment in COPD. It is tempting to speculate, but certainly remains to be established, whether exhaled NO can also predict a positive treatment response to steroids in COPD.

Are patients with low levels of exhaled NO better off?

Apart from monitoring purposes, it is certainly of interest to examine any pathophysiological role of NO in COPD. It is potentially produced by epithelial, endothelial, neuronal, and inflammatory cells through activity of constitutive eNOS and nNOS, or inflammatory induction of iNOS.22 However, we do not know the source of the NO that is detected in the expired air. Even though it was thought that iNOS activity within the airways contributes most to exhaled NO in diseases such as asthma or COPD,23 animal experiments with nNOS knock out mice have shown that constitutive NOS can at least be responsible for 40% of exhaled NO.24 However, even if its cellular source is known, it is far from understood whether local NO within the airways—produced by whatever NOS isoform—mediates pro-inflammatory and/or protective mechanisms.25

What is the relevance of this for COPD? When looking at the data of Corradi et al it appears that ex-smoking patients have higher levels of exhaled NO than currently smoking patients.13 The first explanation for this could be that ex-smoking patients with high levels of exhaled NO represent a selection bias of the clinically worst patients who spontaneously stopped smoking. However, experimental evidence favours an alternative hypothesis. The above results suggest that smoking impairs a normal and important defence mechanism,26 possibly associated with altered immune responses.27 In a previous study we found circumstantial evidence of a protective role of NO during virus induced exacerbations in patients with asthma.28 Interestingly, allergen exposure affects the bronchoprotective NO synthesis in asthmatic subjects.29 The possibility cannot be excluded that such an endogenous defence mechanism will also be impaired in smoking patients with COPD, thereby enhancing the tendency towards exacerbations.30 Indeed, smoking can acutely reduce NO synthesis,31 presumably by direct inhibition of constitutive NOS expression,32 accelerated NO breakdown by superoxide anion yielding the harmful oxidant peroxynitrite33 associated with induced neutrophil activity,34 and/or by a negative feedback mechanism through the high NO levels (100–600 μg) provided by the mainstream smoke of each cigarette.35 The chronic effects of smoking on NO synthesis are still unknown but it has been suggested that smoking induced impairment of NO production can be irreversible.32 This may explain the negative correlation between exhaled NO levels and the number of pack years.13

Clinical implications

There are good reasons to suggest that exhaled NO can be a marker of disease severity and level of control in steroid naive patients with asthma by indirectly reflecting the degree of airways inflammation.23 However, the same cannot be concluded for patients with COPD. In these patients the magnitude of the NO signal is considerably less than in asthma and, most importantly, the major causative agent, cigarette smoke, dramatically masks any tendency towards a disease related rise in exhaled NO levels.31This may not only have consequences for monitoring patients with COPD, but also for the natural history and prognosis of the disease. The positive relationship between exhaled NO levels and FEV1 12 15 36 is in keeping with the hypothesis that endogenous NO represents an important protective mechanism. This could be particularly relevant in patients with COPD who may require local NO release for antimicrobial host defence26 27 or preservation of ventilation/perfusion matching within the lung.37 Interestingly, there is recent evidence that eNOS polymorphism may indeed be involved in the susceptibility for the development of certain phenotypes of COPD such as emphysema associated with α1-antitrypsin deficiency.38

The above might even question the role of inhaled steroids in the maintenance treatment of COPD. Such intervention reduces iNOS activity, which not only might lead to beneficial effects,39 but could also have potentially deleterious consequences in normal or diseased airways.40 Only carefully designed longitudinal studies will enable us to answer these questions arising from the currently available cross sectional data on exhaled NO in COPD.


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