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(Chest. 1999;116:59-64.)
© 1999 American College of Chest Physicians

The Effect of Cigarette Smoking on Exhaled Nitric Oxide in Mild Steroid-Naive Asthmatics*

Geert M. Verleden, PhD; Lieven J. Dupont, MD; Ann C. Verpeut, MD and Maurits G. Demedts, PhD

* From the Department of Respiratory Diseases, University Hospital Gasthuisberg, Leuven, Belgium.

Correspondence to: Geert M. Verleden, PhD, Department of Respiratory Diseases, University Hospital Gasthuisberg, 49, Herestraat, B-3000 Leuven, Belgium; e-mail: geert.verleden{at}uz.kuleuven.ac.be


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objectives: It has been demonstrated previously that exhaled nitric oxide (eNO) is increased in steroid-naive asthmatics and that inhaled steroids reduce eNO in these patients. Cigarette smoking has also been reported to reduce the eNO in healthy volunteers. Recently a correlation has been demonstrated between eNO and airway hyperresponsiveness in steroid-naive, mild asthmatics. We hypothesized that cigarette smoking would reduce the eNO level in steroid-naive asthmatics and might, therefore, affect the correlation between eNO and airway hyperresponsiveness.

Design: Comparison of eNO in healthy smoking and nonsmoking volunteers with the level of eNO in steroid-naive and steroid-treated asthmatics. Correlate the eNO level with the provocative concentration of histamine causing a 20% fall in FEV1 (PC20hist) in the asthmatic smoking and nonsmoking patients.

Setting: University outpatient asthma clinic.

Patients and methods: eNO levels and PC20hist were measured in three different asthmatic patient groups (group A = 29 steroid-naive, nonsmoking asthmatics; group B = 19 steroid-treated, nonsmoking asthmatics; and group C = 13 smoking, steroid-naive asthmatics) and in two healthy volunteer groups (group D = 18 nonsmoking; and group E = 16 smoking).

Results: eNO in group A was significantly increased compared with the values in groups B and D (21.8 ± 12.7, 12.8 ± 4.9, and 10.6 ± 2.2 parts per billion [ppb], respectively). Cigarette smoking decreased eNO in healthy volunteers (7.4 ± 1.8 ppb, group E) as well as in steroid-naive asthmatics (12.7 ± 5.1 ppb, group C). There was a significant correlation between eNO and PC20hist in group A (r = -0.45, p < 0.05); this correlation was, however, lost in both groups B and C.

Conclusion: Cigarette smoking and inhaled steroids reduce the eNO in patients with mild asthma to a comparable extent. Because the correlation between eNO and airway hyperresponsiveness was lost in steroid-treated and smoking, steroid-naive asthmatics, we question the value of eNO as a marker of airway inflammation, at least in mild asthmatics who are already being treated with inhaled steroids or who are currently smoking.

Key Words: airway inflammation • cigarette smoking • exhaled nitric oxide • inhaled steroids • mild asthma


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Nitric oxide (NO) plays a key role in the airways as a vasodilator, neurotransmitter, and inflammatory mediator. Recently, it has been demonstrated that NO is produced in increased amounts in patients with asthma and in other inflammatory airway diseases.1 This increased NO production in asthmatics is probably due to inducible NO synthase (iNOS) in inflammatory and epithelial cells from the airways, since a specific inhibitor of iNOS reduces the amount of exhaled NO (eNO) in these patients.2 Increased NO production in the airways of asthmatics may indirectly result in eosinophilic inflammation by promoting the development of Th2 lymphocytes.3 It has already been reported that inhaled steroids decrease the amount of eNO in asthmatics through the inhibition of iNOS.4 Cigarette smoking also reduces eNO in healthy volunteers, possibly through the inhibition of the endogenous NO production,5 although this remains to be fully elucidated at the moment. Furthermore, it has been suggested that measurement of eNO could be used as a noninvasive method to assess airway inflammation,6 and recently we have demonstrated that there is indeed a relationship between eNO and airway hyperresponsiveness (measured as the provocative concentration of histamine causing a 20% decrease in FEV1 [PC20hist]),7 which is known to correlate with airway inflammation.8 Because inhaled steroids reduce the eNO, and the correlation between eNO and PC20hist was lost under steroid treatment,8 we hypothesized that the eNO would be reduced in smoking steroid-naive asthmatics also, leading to a loss of this correlation and further questioning of the value of eNO as a marker of airway inflammation in asthma.

We, therefore, undertook the present study, on the one hand, to examine the effect of cigarette smoking on eNO in patients with steroid-naive asthma and to compare this with the effect of cigarette smoking in healthy volunteers and with inhaled steroids in patients with mild asthma and, on the other hand, to correlate the eNO level in these different patient groups, with the presence of airway hyperresponsiveness measured as PC20hist.


   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Subjects were recruited from outpatients (University Outpatient Asthma Clinic) in whom asthma was diagnosed based on their symptomatology (ie, periodic cough, dyspnea or wheeze, or a combination) and the presence of a positive histamine challenge test with reversible airway obstruction (> 15% increase in FEV1 after albuterol, 200 µg). Sixty-one patients (29 were female and 32 were male; mean [± SD] age, 36 ± 16 years old) were included in the study from whom informed consent was obtained. Subjects had to be either active smokers (>= 1 cigarette a day) or never smokers with an FEV1 > 80% predicted. All patients underwent spirometry according to the European Respiratory Society (ERS) Guidelines.9 Subsequently, eNO was measured, and they underwent a standardized histamine challenge test.10

PC20hist was calculated by linear interpolation. The patients were then further subdivided according to their smoking habits and their use of inhaled steroids (all patients were receiving short-acting inhaled ß2-adrenergic agonists as needed). Group A consisted of steroid-naive, nonsmoking asthmatics (group A; n = 29); group B were nonsmoking asthmatics receiving inhaled steroid treatment (n = 19; [mean ± SD] dose of inhaled steroids, 947 ± 116 µg of beclomethasone dipropionate or equivalent); and group C were steroid-naive asthmatic smokers (n = 13) with a mean daily cigarette consumption of 17 ± 6 during 14 ± 6 years. All patients completed a questionnaire regarding their respiratory complaints and current use of medication (asthma severity score [ASS]).7 Thirty-four healthy volunteers (19 were female and 15 were male; [mean ± SD] age, 33 ± 11 years old) were recruited from the staff of the University Hospital Gasthuisberg (Leuven, Belgium) and acted as the control group. Eighteen of them were nonsmokers (group D), whereas 16 were active smokers (group E) with a mean (± SD) daily cigarette consumption of 18 ± 7 during 16 ± 9 years. They had absolutely no history of cardiovascular, respiratory, or other underlying diseases and did not take medication regularly. They had no respiratory complaints and had normal spirometric results. Neither the patients nor the volunteers had a history of upper-respiratory tract infection for at least 6 weeks before the study.11 They did not consume any alcohol-containing beverages,12 and they did not use inhaled short-acting ß2-adrenergic agonists in the 8 h before eNO and PC20hist measurements. Smokers refrained from smoking for at least 1 h before the measurement of eNO, which was a sufficient time to exclude interference from the cigarette smoke itself.5

eNO was measured during a single-breath exhalation with a chemiluminescence analyzer (Ecophysics CLD700 AL Med; Eco Physics; Dürnten, Switzerland). Measurements were performed according to ERS guidelines.13 In brief, a slow vital capacity maneuver was performed against a fixed expiratory resistance, with a target gauge of 20 cm H2O to close the vellum and to create a constant flow of 200 mL/s.7 Exhaled air was led via a nonrebreathing valve (Hans Rudolph; Kansas City, MO) into a Teflon tubing system connected to the analyzer. Air was continuously sampled from the exhalation limb of the system, with a sampling rate of 0.7 L/min and a response time of 1 s. Results were displayed on a chart recorder, and the plateau level was noted. Three reproducible recordings (ie, < 15% variation) with a 2-min interval were performed, and the highest of the three recordings was taken as the eNO value. All eNO levels are reported in parts per billion (ppb). The detection limit for eNO was 1 ppb, and all measurements were performed in the same chamber around the same time of the day. A daily NO zeroing was performed using NO-free air. Two-point calibration was performed with a certified concentration of NO (100 ppb) balanced with N2, according to the ERS guidelines.13 Day-to-day reproducibility was assessed in preliminary experiments. The variability between eNO levels measured at the same time of day on three consecutive days was < 10%.7

The Kruskall-Wallis nonparametric analysis of variance test and Dunn's multiple comparisons test were used to assess significant differences in age, FEV1, and eNO among the five different groups or the three asthmatic groups (PC20hist). Logarithmic transformation was done for eNO and PC20hist values before analysis. Correlations were made with Spearman's rank test. Linear regression was done with the least-squares method. A p value of < 0.05 was considered significant.


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
The characteristics of the patients and the healthy volunteers (mean [± SD]) are summarized in Table 1 . There were no significant differences in age and FEV1 among the five different groups and in ASS and PC20hist among the three asthmatic groups, although there was a trend for the PC20hist to be lower in group A.


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  		Table 1. Demographic and Functional Data of the Different Groups*

 
There was, however, a significant difference in eNO among the five different groups (p < 0.001). eNO in the steroid-naive asthmatics (group A) was significantly higher (21.8 ± 12.7 ppb) compared with the eNO level in steroid-treated asthmatics (group B, 12.8 ± 4.9 ppb) and the eNO level of the steroid-naive, smoking asthmatics (group C, 12.7 ± 5.1 ppb; p < 0.05).

The eNO in nonsmoking volunteers (group D) was 10.6 ± 2.2 ppb, which was significantly different than the value in steroid-naive asthmatics (group A, p < 0.01) but was not significantly different from the eNO values in steroid-treated asthmatics (group B) and in smoking, steroid-naive asthmatics (group C).

In the smoking volunteers (group E), the eNO was lower than in the nonsmoking volunteers (group D), with a value of 7.4 ± 1.8 and 10.6 ± 2.2 ppb, respectively, although this was not significantly different. We found no correlation between the amount of cigarettes that were smoked daily and the eNO value. There was also no significant difference in eNO between the steroid-treated asthmatics (group B, 12.8 ± 4.9 ppb) and the smoking, steroid-naive asthmatics (group C, 12.7 ± 5.1 ppb). There was, however, still a significant difference between the eNO in the nonasthmatic smokers (group E) and smoking, steroid-naive asthmatics (group C, 7.4 ± 1.8 vs 12.7 ± 5.1 ppb; p < 0.05; Fig 1 ).



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  		Figure 1. Values of eNO (in ppb) in the different groups: group A (steroid-naive, nonsmoking asthmatics), group B (steroid-treated, nonsmoking asthmatics), group C (steroid-naive, smoking asthmatics), group D (nonsmoking, healthy volunteers), and group E (smoking, healthy volunteers). Significance: * p < 0.05, ** p < 0.01, *** p < 0.001.

 
There was a significant correlation between eNO and PC20hist in group A (r = -0.45; p < 0.05); however, in groups B and C, this correlation was lost (Fig 2 ).



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  		Figure 2. Relationship between eNO (in ppb) and PC20hist (in mg/mL) in group A (steroid-naive, nonsmoking asthmatics; r = -0.45, p < 0.05; top, A); group B (steroid-treated, nonsmoking asthmatics; r = -0.151, p = not significant; bottom left, B); and group C (steroid-naive, smoking asthmatics; r = 0.19, p = not significant; bottom right, C).

 

   Discussion
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In this study, we have again confirmed that eNO is higher in steroid-naive asthmatics compared with steroid-treated asthmatics.1 7 14 15 For the first time (to our knowledge), we have demonstrated that eNO is lower in smoking, steroid-naive asthmatics compared to nonsmoking, steroid-naive asthmatics, despite the fact that they were in an apparently comparable clinical condition (ie, comparable ASS, PC20hist, and FEV1). We also found that healthy smokers have a reduced eNO compared with nonsmokers, which is in agreement with other investigators,5 15 16 and that smoking reduced the eNO to the same extent as inhaled steroids in steroid-naive, mild asthmatics. However, we could not find a correlation between the amount of cigarettes consumed daily and the value of eNO, in contrast to Kharitonov et al.5 This could be due to several factors. One factor is the method of eNO measurements. Kharitonov et al5 measured peak eNO, whereas we measured the plateau level, although this mechanism does not seem to be important enough to explain the difference.16 In our study, an expiratory resistance was used, according to the ERS guidelines on eNO measurements, to avoid contamination of eNO with NO originating from the nasopharynx.13 Kharitonov et al5 did not implement an expiratory resistance. Second, our smoking asthmatics had a high daily cigarette consumption, with as many as 75% of them smoking > 15 cigarettes a day, whereas in the study done by Kharitonov et al,5 there was a big variation in cigarette consumption, with 15 volunteers (37%) smoking 1 to 10 cigarettes a day and approximately 50% smoking >= 15 cigarettes a day.

We also confirmed the correlation between eNO and airway hyperresponsiveness (PC20hist) in the nonsmoking, steroid-naive asthmatic patients and the lack of correlation in steroid-treated, nonsmoking asthmatics, in line with our previous data.7 The present study further demonstrated that the correlation between eNO and PC20hist was lost in smoking, steroid-naive mild asthmatics.

All three asthmatic groups in our study had a comparable FEV1, PC20hist, and ASS, suggesting that they were all controlled to the same extent. Asthmatics in group B needed inhaled steroids (mean [± SD] dose, 947 ± 116 µg of beclomethasone dipropionate or an analog) to obtain that level of control, suggesting that their asthma was indeed more severe compared with the other asthma groups. Patients in groups A and C, however, did not differ with regard to parameters of asthma severity, such as FEV1, PC20hist, ASS, and use of medication, despite the fact that the level of eNO in group C was significantly lower compared with group A. Because it is known that cigarette smoking itself increases airway hyperresponsiveness and symptomatology, this might suggest that smoking, steroid-naive asthmatics had, in fact, less severe underlying asthma than nonsmoking, steroid-naive asthmatics, which could account for the lower eNO. Indeed, when we compare the eNO level in smoking steroid-naive asthmatics (group C) and smoking volunteers (group E), we find an increase in eNO of ± 72% in group C (from 7.4 to 12.7 ppb), which seems to be lower than the increase of eNO in the steroid-naive nonsmoking asthmatics (group A) compared with the nonsmoking volunteers (group D; from 10.6 to 21.8; ± 106%). Although a difference in asthma severity among the three groups is likely, we do not think that confounding differences of severity alone can explain the difference in eNO levels between the asthma groups.

Recently, we have demonstrated that measurement of eNO allowed us to discriminate, among patients with respiratory complaints suggestive of mild asthma, between those with and without airway hyperresponsiveness.7 This study would contradict these findings, because the eNO level in smoking, steroid-naive asthmatics (with a mean PC20hist of 2.1 mg/mL) was comparable to the eNO level in nonsmoking healthy volunteers (with a PC20hist of > 8 mg/mL). Some caution is needed when interpreting these data, because the eNO level of smoking, steroid-naive asthmatic patients remains significantly increased, compared with the eNO level of healthy, smoking volunteers.

NO is formed from L-arginine by the activity of NO synthase (NOS). At least three independent NOS enzymes have been identified in the airways: a constitutive NOS (cNOS), including an endothelial form and a neuronal form, and an iNOS. The constitutive endothelial form mediates endothelium-dependent vasodilator responses, whereas a neuronal form is involved in neural bronchodilatation.17 The iNOS enzyme is induced by pro-inflammatory cytokines in the epithelial cells and macrophages in the airways18 and may be important in the defense of the respiratory tract against inhaled infectious agents.19 Increased NO production in the airways of asthmatics has several deleterious effects. NO may stimulate the neurogenic inflammatory process and may indirectly stimulate eosinophilic infiltration into the airways by promoting the development of Th2 lymphocytes and, hence, the production of eosinophilotropic cytokines.3

In this study and also in previous studies,5 16 it was demonstrated that cigarette smoking reduces the eNO, not only in steroid-naive asthmatics, but also in healthy smoking volunteers. The exact mechanism by which this occurs is still debated. It was reported recently20 that exogenous NO could reversibly inhibit the cNOS from rat cerebellum and from bovine aortic endothelial cells, with the latter being responsible for an impaired endothelial cell function21 and, hence, playing a role in the development of pulmonary hypertension. Cigarette smoking indeed causes a transient decrease in eNO, which returns to baseline levels within 15 min.5 This can be explained by the high levels of NO contained in cigarette smoke. The more pronounced baseline reduction in eNO in smokers is more consistent with a reduction in cNOS or even in iNOS.5 This might have several adverse effects since endogenous NO has antimicrobial activities19 and is important for the normal ciliary function in the airway.22 Decreased endogenous NO production also attenuates chemotaxis of polymorphonuclear leukocytes in vitro23 and may have a role in the development of atherosclerosis and restenosis after endothelial injury.24

It is well known that cigarette smoke is a frequent cause of indoor pollution and that infants of smoking parents are affected more often by respiratory diseases than nonexposed children.25 Also, it has been demonstrated that a reduction of the smoking pattern of the parents ameliorates the asthma severity of their children.26 Cigarette smoke can also induce an increase in bronchial hyperresponsiveness, suggesting an increased airway inflammation, which may persist for up to 14 days.27 Cigarette smoke is further known to inhibit the enzyme neutral endopeptidase, which degrades tachykinins in the airway and which may result in exaggerated neurogenic inflammation.28 Long-term cigarette smoking is associated with elevated tissue levels of calcitonin gene-related peptide, suggesting up-regulation of C-fiber function and peptide synthesis, which may contribute to airway hyperresponsiveness.29

Although in this study, cigarette smoking, as well as inhaled steroids, reduced the amount of eNO in steroid-naive asthmatics to a comparable extent, cigarette smoking remains to be considered as deleterious. Based on the present data, we suggest that the effect of cigarette smoking on eNO only further questions the value of eNO as a noninvasive marker of airway inflammation in asthmatics,6 since there only seems to be a correlation between eNO and airway hyperresponsiveness (as a measure of airway inflammation) in steroid-naive, nonsmoking asthmatics, whereas the correlation is absent in steroid-treated7 and in smoking, steroid-naive asthmatics.

In conclusion, we have demonstrated that cigarette smoking not only reduces the eNO in healthy volunteers, but also in steroid-naive asthmatics in whom the eNO level is normally increased via up-regulation of iNOS. Moreover, cigarette smoking and inhaled steroids reduce the eNO level in those patients to a comparable extent. The exact mechanism of this action is still unknown. Since we were not able to demonstrate a correlation between eNO and PC20hist in smoking, steroid-naive asthmatics, we have some doubts as to whether eNO measurement can be regarded as a good marker of airway inflammation, at least in some asthmatic patient groups (eg, steroid-treated and smoking). At the moment, there is no clear explanation, but these findings definitely require further investigation.


   Footnotes
 
Funded by the Broere Foundation. Dr. Verleden is the holder of the GlaxoWellcome Leerstoel in Respiratoire Farmacologie at the Catholic University of Leuven, Belgium.

Abbreviations: ASS = asthma severity score; cNOS = constitutive nitric oxide synthase; eNO = exhaled nitric oxide; ERS = European Respiratory Society; iNOS = inducible nitric oxide synthase; NO = nitric oxide; NOS = NO synthase; PC20hist = the provocative concentration of histamine causing a 20% decrease in FEV1; pbb = parts per billion

Received for publication August 18, 1998. Accepted for publication January 13, 1999.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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