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(Chest. 2003;123:993-997.)
© 2003 American College of Chest Physicians

Effect of Cigarette Smoking on Airway Responsiveness to Adenosine 5'-Monophosphate in Subjects With Allergic Rhinitis*

Luis Prieto, PhD; Valentina Gutiérrez, PhD; Sonia Uixera, MD and J. Manuel Bertó, PhD

* From the Sección de Alergología and Universidad de Valencia, Valencia, Spain.

Correspondence to: Luis Prieto, PhD, Sección de Alergología, Hospital Universitario Dr. Peset, C/Gaspar Aguilar 90, 46017 Valencia, Spain; e-mail: prieto_jes{at}gva.es


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objectives: The objective of this study was to determine differences in airway responsiveness to adenosine 5'-monophosphate (AMP) between smokers and nonsmokers with allergic rhinitis.

Methods: A total of 41 adults with allergic rhinitis (16 smokers and 25 nonsmokers) were challenged with increasing concentrations of methacholine and AMP. Airflow was assessed after each concentration, and the response to each bronchoconstrictor agent was measured by the provocative concentration required to produce a 20% fall in FEV1 (PC20).

Results: The geometric mean PC20 AMP values were significantly lower in smokers than in nonsmokers: 72.4 mg/mL (95% confidence interval [CI], 33.9 to 154.9) vs 204.2 mg/mL (95% CI, 120.2 to 346.7) [p = 0.021]. The proportion of subjects with bronchoconstriction in response to AMP was higher in smokers (12 of 16 subjects) than in nonsmokers (7 of 25 subjects) [p = 0.005].

Conclusions: We conclude that smokers with allergic rhinitis have a greater AMP sensitivity than nonsmokers.

Key Words: adenosine 5'-monophosphate • allergic rhinitis • methacholine • smoking


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
It is now clear from a number of studies that an increased responsiveness to methacholine is frequently observed in nonasthmatic subjects with allergic rhinitis.1 Besides methacholine, an important proportion of subjects with allergic rhinitis also have bronchoconstriction in response to inhaled adenosine 5'-monophosphate (AMP).2 Since inhaled AMP acts indirectly by binding to adenosine receptors on mast cells causing them to degranulate and release mediators,3 it has been claimed that, in nonasthmatic subjects with allergic rhinitis, the response to AMP is more indicative of airway wall inflammation than the response to methacholine.4 5

There is now evidence6 that smoking is associated with increased airway responsiveness to AMP in nonatopic subjects with COPD. In contrast, smoking does not increase sensitivity to AMP in subjects with allergic asthma.7 This suggests that inflammatory changes in the airways induced by smoking determine the AMP responsiveness in COPD, but not in allergic asthma. Since inflammatory changes in the lower airways, such as eosinophil accumulation and activation of mast cells, are seen in nonasthmatic subjects with allergic rhinitis,8 we wished to evaluate the additional influence of smoking on airway responsiveness to AMP in subjects with allergic rhinitis.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Subjects
Sixteen current smokers and 25 nonsmokers with allergic rhinitis were included in the study. Subjects were recruited from our outpatient allergy clinic. Subjects with allergic rhinitis were defined as those individuals with a characteristic history of perennial or seasonal rhinitis (rhinorrhea, sneezing, nasal obstruction, and pruritus) and who also had skin sensitization to perennial or seasonal allergens. Nonsmokers were individuals who had never smoked; current smokers were those who smoked at least one cigarette a day. No subject had a history of asthma (wheezing, dyspnea, chest tightness, chronic cough, or exercise wheeze), and none had history of chronic bronchitis, emphysema, or respiratory tract infections during the 4 weeks before the study. The subjects’ baseline FEV1 was > 80% predicted. The study protocol was approved by the local ethics committee, and written informed consent was obtained from all participants.

Study Design
The study was an open design. Subjects attended the laboratory on three visits at the same time of the day (± 2 h). On the first visit, subject characteristics were documented by a general questionnaire on upper and lower respiratory symptoms, history of asthma or other relevant diseases, and medications required for nasal symptoms. Skin-prick tests for common inhalant allergens and spirometric measurements were performed. On the second visit, a methacholine inhalation test was performed, followed after 7 to 11 days by an AMP inhalation test. Subjects were instructed to withhold their treatment for at least 4 weeks (nasal topical corticosteroids and nasal topical cromoglycate) and 3 days (antihistamines) prior to each challenge.

Skin-Prick Testing
Atopic status was measured by skin-prick testing using 13 common allergens applied to the forearm. The allergens (ALK-Abelló; Madrid, Spain) tested were house dust mites (Dermatophagoides pteronyssinus and Dermatophagoides farinae), household pets (cat and dog), pollens (mixed grass, Platanus orientalis, olive, mixed weed, and Parietaria judaica) and molds (alternaria, Aspergillus fumigatus, Cladosporium, and Penicillium). Histamine and glycerinated saline solution were used as positive and negative controls. A skin-prick test result was considered positive if the mean wheal diameter was at least 3 mm.

Pulmonary Function
Spirometry was performed with a calibrated dry rolling seal spirometer (Model 2130; SensorMedics; Yorba Linda, CA) according to standardized guidelines.9 Baseline FEV1 and FVC were measured until three reproducible recordings differing < 5% were obtained. Maneuvers were accepted as technically satisfactory if the back-extrapolated volume was < 0.15 L or 5% FVC, and if the expiratory time was at least 6 s. Highest values were used for analysis. Reference values were those of the European Community for Coal and Steel.10

Inhalation Challenge Tests
Inhalation provocation tests were performed according to a 2-min tidal breathing method11 with the nose clipped, as previously described.2 The solutions were administered at room temperature as aerosols generated from a starting volume of 2 mL via nebulizers (Model 1720; Hudson; Temecula, CA). The mean ± SD outputs of two nebulizers were determined by weighing each nebulizer before and after 2-min nebulizations on six occasions; these were 0.14 ± 0.02 mL/min for the methacholine nebulizer and 0.13 ± 0.03 mL/min for the AMP nebulizer.

Methacholine chloride and AMP (Sigma Chemical; St. Louis, MO) were dissolved in normal saline solution to produce doubling concentrations range of 0.39 to 200 mg/mL for methacholine and from 1.56 to 400 mg/mL for AMP, and immediately used for bronchial challenge. The first nebulization administered in each challenge was normal saline solution, and the postsaline solution FEV1 was used as the baseline for the calculation of subsequent percentage fall in FEV1. After challenge with saline solution, doubling concentrations of methacholine chloride or AMP were inhaled. Because of the effect of a deep inspiration on subsequent airway tone,12 only one measurement for FEV1 was performed 60 to 90 s after inhalation of each concentration unless the forced expiratory maneuver was judged technically unsatisfactory. The test was interrupted when a 20% decrease in FEV1 from the postsaline solution value was recorded or when the highest concentration was reached. A log concentration-response curve was constructed for each challenge, and the provocative concentration (methacholine or AMP) that caused a 20% fall in FEV1 (PC20) was calculated by logarithmic interpolation.13

Data Analysis
All PC20 values were log-transformed before analysis and presented as geometric means with 95% confidence intervals (CIs). All other numerical variables are reported as arithmetic means with 95% CIs.

A methacholine PC20 value of 200 mg/mL was assigned to four smoking patients and nine nonsmoking patients in whom FEV1 dropped < 20% even when the highest concentration of methacholine was used. Further, a PC20 value for AMP could not be calculated in 4 smoking patients and 18 nonsmoking patients. On these occasions, the PC20 value was censored to the highest concentration of AMP administered (400 mg/mL).

Comparisons between the groups were done using the Student t test for numerical data and the Fisher exact test for categorical data. Probability values are two sided, and p values < 0.05 were considered statistically significant. Data were analyzed with a statistical software package (InStat for Windows, Version 3.05; GraphPad Software; San Diego, CA).


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
The two groups (Table 1 ) did not differ with respect to age, sex, duration of nasal symptoms, prevalence of skin sensitization to perennial or seasonal allergens, and baseline pulmonary function. Mean baseline FEV1 values were not significantly different within the two groups before the two different provocation tests.


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  		Table 1. Patient Characteristics*

 
The geometric mean PC20 AMP values were significantly lower (Fig 1 ) in smokers than in nonsmokers: 72.4 mg/mL (95% CI, 33.9 to 154.9) vs 204.2 mg/mL (95% CI, 120.2 to 346.7) [p = 0.021]. The geometric mean PC20 methacholine values (Fig 2 ) were also significantly lower in smokers than in nonsmokers: 7.1 mg/mL (95% CI, 2.3 to 21.9) vs 30.2 mg/mL (95% CI, 14.4 to 66.1) [p = 0.023].



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  		Figure 1. Individual values for PC20 AMP in smokers and nonsmokers with allergic rhinitis. Shaded area indicates PC20 values > 400 mg/mL; horizontal lines indicate geometric means.

 


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  		Figure 2. Individual values for PC20 methacholine in smokers and nonsmokers with allergic rhinitis. Shaded area indicates PC20 values > 200 mg/mL; horizontal lines indicate geometric means.

 
The proportion of subjects with increased responsiveness to methacholine11 (PC20 <= 8 mg/mL) was higher in smokers (11 of 16 patients) than in nonsmokers (7 of 25 patients) [p = 0.02]. The proportion of subjects with bronchoconstriction in response to AMP (PC20 <= 400 mg/mL) was also higher in smokers (12 of 16 patients) than in nonsmokers (7 of 25 patients) [p = 0.005].


   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In this study, we have found that bronchoconstriction develops in a significant proportion of subjects with allergic rhinitis in response to both methacholine and AMP. Furthermore, the results of the present study indicate that smokers with allergic rhinitis have a greater sensitivity to inhaled AMP than nonsmokers with allergic rhinitis.

Our findings are in line with previous studies that demonstrated an increased responsiveness to methacholine1 11 14 and AMP2 15 16 in a proportion of nonsmokers with allergic rhinitis. Furthermore, the present report, by showing that smokers with allergic rhinitis have a higher prevalence of airway hyperresponsiveness to methacholine, confirms the observations of the study of Buczko and Zamel.17

To the best of our knowledge, no previous information is available on differences in airway responsiveness to inhaled AMP between smokers and nonsmokers with allergic rhinitis. Our results indicate that airway responsiveness to inhaled AMP is significantly higher in smokers than in nonsmokers. This suggests that, at least in subjects with allergic rhinitis, smoking and atopy have a combined effect to increase airway responsiveness to AMP.

We do not believe that our findings can be explained by measurement errors, since the results were obtained after carefully addressing such aspects of methodology as study design and measurement procedures. Baseline airway caliber as assessed by FEV1 prior to bronchial challenge was not significantly different between the two study groups. Thus, effects caused by differing baseline airway caliber on the subsequent determination of PC20 could be eliminated. This is relevant to the evaluation of PC20 because airway geometry has an important influence on assessing airway responsiveness to a bronchoconstrictor agent.18 In addition, challenges were carried out at the same time of the day, thus ruling out a possible influence of circadian variations on airway responsiveness. Finally, none of the subjects was being treated with medications that could have affected the response to bronchoconstrictor agents.

However, there were limitations to our study, which are important to consider. First, estimation of the airway responsiveness was complicated because four smoking subjects (25%) and nine nonsmoking subjects (36%) had PC20 methacholine values above the upper limit of measurement. In addition, 4 smoking subjects (25%) and 18 nonsmoking subjects (72%) had PC20 AMP values above the upper limit of measurement. PC20 values of 200 mg/mL for methacholine and 400 mg/mL for AMP were assigned to these subjects, but this gives an underestimation of their true PC20 value. Given these restrictions, the significance of the differences in the responses of the two groups is almost certainly an underestimation. Second, our subjects with pollen-induced rhinitis were tested during a period of natural pollen exposure, and there is convincing evidence that in this group of subjects, natural allergen exposure during a pollen season results in increased responsiveness to both methacholine19 and AMP.20 However, the proportion of subjects sensitized to pollen allergens was similar in both groups, and we do not believe that our findings can be explained by differences in natural allergen exposure. Finally, inhalation challenges were not performed randomly, and there is a slight possibility that the methacholine challenge might have influenced the AMP test. This seems to be unlikely, since the study days were separated by 7 to 11 days.

The association between airway inflammation and bronchial hyperresponsiveness in asthma is a widely accepted concept,21 whereas the pathogenesis of bronchial hyperresponsiveness associated with allergic rhinitis is still debated. In particular, it is not known whether the increased bronchial responsiveness in allergic rhinitis is, as in asthma, associated with airway inflammation or if it is linked to other mechanism(s), such as the nasal-bronchial reflex, mouth breathing because of nasal obstruction, or postnasal drip of mediators. Inflammatory changes such as eosinophil accumulation22 and enhanced collagen deposition in the lower airways23 are seen in patients with allergic rhinitis who have no symptoms of asthma. All these findings support the hypothesis of a subclinical bronchial inflammation associated with airway hyperresponsiveness in subjects with allergic rhinitis. If bronchoconstriction induced by AMP depends, at least in part, on the state of activation of airway mast cells,3 24 it is interesting to speculate that AMP responsiveness may be a more direct marker of allergic airway inflammation in subjects with allergic rhinitis than direct bronchoconstrictors such as histamine or methacholine. In line with these speculations, Polosa et al4 demonstrated that in nonasthmatic subjects with allergic rhinitis, airway responsiveness to AMP is more strongly related to sputum eosinophilia than is methacholine.

In the absence of information about inflammatory changes in the airways of patients participating in the present study, we are unable to offer an explanation for the increased responsiveness to AMP in smokers with allergic rhinitis. However, we can propose some hypotheses. Increased histamine levels in the BAL fluid25 and activated mast cells in bronchial wall biopsy specimens8 are seen in nonasthmatic subjects with allergic rhinitis. In addition, increased levels of the mast cell products histamine and tryptase are detected in the BAL fluid of healthy smokers,26 suggesting an increased susceptibility of airway mast cells to release their mediators. Therefore, if bronchoconstriction induced by AMP is due, at least in part, to the release of mediators from preactivated mast cells,3 it is interesting to speculate that increased responsiveness to AMP in smokers with allergic rhinitis is determined by either increased number and/or activation state of airway mast cells. However, at variation with allergic rhinitis patients, nonsmokers with asthma have increased responsiveness to AMP compared with that in smokers.7 Thus, the effect of smoking on AMP-induced bronchoconstriction in subjects with asthma appears to be different from that in allergic rhinitis. Future studies should establish the factors that determine the presence of bronchoconstriction in response to AMP in smokers and nonsmokers with allergic rhinitis or asthma, and markers of inflammation, more direct than responsiveness to indirect agonists, are needed to give more insight in this issue.


   Acknowledgements
 
The authors thank R. Rojas and B. Camps for technical assistance, and Laboratorios Bial-Arístegui (Bilbao, Spain) for their help and collaboration.


   Footnotes
 
Abbreviations: AMP = adenosine 5'-monophosphate; CI = confidence interval; PC20 = provocative concentration causing a 20% fall in FEV1

This study is part of the NAOMI Project (publication No. 11).

Received for publication May 21, 2002. Accepted for publication September 3, 2002.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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L. Prieto, I. Reig, R. Rojas, A. Ferrer, and J. Domenech
The effect of challenge method on sensitivity and reactivity to adenosine 5'-monophosphate in subjects with suspected asthma.
Chest, November 1, 2006; 130(5): 1448 - 1453.
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