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(Chest. 2001;120:1917-1922.)
© 2001 American College of Chest Physicians

Smoking and Airway Inflammation in Patients With Mild Asthma*

George W. Chalmers, MD; Kirsten J. MacLeod, BSc; Lorna Thomson, BA; Stuart A. Little, MB, ChB:; Charles McSharry, PhD and Neil C. Thomson, MD

* From the Departments of Respiratory Medicine (Drs. Chalmers, Little, and Thomson, and Ms. Thomson) and Immunology (Ms. MacLeod and Dr. McSharrry), Western Infirmary, Glasgow, UK.

Correspondence to: Neil C. Thomson, MD, Department of Respiratory Medicine, Western Infirmary/Gartnavel General Hospital, 1053 Great Western Rd, Glasgow G12 0YN, UK; e-mail nct1f@clinmed.gla.ac.uk


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objectives: Cigarette smoking is common in asthmatic patients, and we investigated the impact of cigarette smoking on airway inflammation in asthma.

Design: Single-center observational study of airway inflammation in asthmatic and healthy smokers and nonsmokers.

Setting: Asthma research unit in a university hospital.

Patients or participants: Sixty-seven asthmatic and 30 nonasthmatic subjects classified as smokers or nonsmokers. Asthmatics had chronic, stable asthma and were not receiving inhaled or oral steroids at the time of the study.

Interventions: We examined induced-sputum cell counts and levels of interleukin (IL)-8 and eosinophilic cationic protein (ECP). Bronchial hyperreactivity was assessed using methacholine challenge.

Measurements and results: Asthmatic smokers had higher total sputum cell counts than nonsmoking asthmatics and both smoking and nonsmoking healthy subjects. Smoking was associated with sputum neutrophilia in both asthmatics and nonasthmatics (median, 47% and 41%, respectively) compared with nonsmokers (median, 23% and 22%, respectively), and sputum IL-8 was increased in smokers compared with nonsmokers, both in subjects with asthma (median, 945 pg/mL vs 660 pg/mL, respectively) and in healthy subjects (median, 1,310 pg/mL vs 561 pg/mL, respectively). Sputum eosinophils and ECP levels were higher in both nonsmoking and smoking asthmatics than in healthy nonsmokers. In smoking asthmatics, lung function (FEV1 percent predicted) was negatively related to both sputum IL-8 (r = - 0.52) and sputum neutrophil proportion (r = - 0.38), and sputum IL-8 correlated positively with smoking pack-years (r = 0.57) and percent neutrophil count (r = 0.51).

Conclusions: In addition to the eosinophilic airway inflammation observed in patients with asthma, smoking induces neutrophilic airway inflammation; a relationship is apparent between smoking history, airway inflammation, and lung function in smoking asthmatics.

Key Words: airway inflammation • asthma • interleukin-8 • neutrophils • smoking


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Asthma is a chronic inflammatory condition characterized by inflammatory cell infiltration of the airways with activated T cells and eosinophils, reversible bronchoconstriction, and bronchial hyperresponsiveness, with resultant respiratory symptoms. The presence of airway inflammation has been demonstrated even in patients with newly diagnosed,1 mild,2 or intermittent3 disease. Studies investigating airway inflammation in asthma have concentrated on nonsmokers, but smoking is common in patients with asthma. Epidemiologic evidence4 suggests that smoking adversely affects an already accelerated decline in lung function in asthma, although the mechanism by which this occurs is not yet clear.

Cigarette smoke has the capacity to damage the bronchi in a number of ways, including direct toxicity to the bronchial epithelium, oxidative damage, recruitment of inflammatory cells, and increased epithelial permeability,5 and smoking is associated with the development of airflow limitation in susceptible subjects. In the absence of atopy, smoking is related to bronchial hyperresponsiveness in nonasthmatics,6 and results in airway inflammation,7 the severity of which has been shown8 to be related to the severity of airflow limitation in nonasthmatics. Cigarette smoke induces the release of the potent neutrophil chemoattractant interleukin (IL)-8 from cultured human bronchial epithelial cells,9 and BAL specimens from nonasthmatic smokers have greater concentrations of neutrophils, macrophages, and a number of cytokines, including IL-1ß, IL-6, IL-8, and monocyte chemoattractant protein-1 than nonsmokers, with evidence of a cigarette dose-related relationship for some of these factors.10 The above-mentioned studies examining the effect of smoking on airway inflammation were performed using nonasthmatic cells or subjects, and we are not aware of any studies that have examined the influence of cigarette smoking on airway inflammation in patients with asthma.

The use of induced sputum to assess airway inflammation has been shown11 to be valid, reproducible, and reliable as a method for assessing airway inflammation in patients with asthma, although the volume of sputum obtained does not allow analysis of as many factors as might be possible with BAL. We have used sputum induction to obtain samples to assess the cellular profile of sputum in asthmatic and nonasthmatic smokers, focusing on neutrophil numbers along with sputum levels of the neutrophil chemoattractant IL-8, since IL-8 and neutrophils are known to be of importance in the airway inflammation observed in airway diseases associated with cigarette smoking.12


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Subjects
Thirty nonasthmatic and 67 asthmatic subjects were further classified according to their smoking habits. Asthmatic subjects had stable symptoms at the time of study, and no history within the preceding 2 months of respiratory infection, or antibiotic or oral corticosteroid use, and were treated only with inhaled bronchodilators as required. Asthma was defined according to the American Thoracic Society definition,13 baseline lung function was recorded and, in asthmatic subjects, nonspecific bronchial hyperresponsiveness was established using a methacholine challenge test, with all asthmatic subjects having a provocative concentration of methacholine causing a 20% fall in FEV1 (PC20) of < 8 mg/mL at screening. None of the nonasthmatic subjects had asthmatic symptoms or required inhalational therapy. One subject in the asthmatic smoking group had a history of productive cough that would fit with diagnostic criteria for chronic bronchitis, but she had symptoms suggestive of variable airflow obstruction, increase in FEV1 of 16% following inhaled bronchodilator treatment, and bronchial hyperresponsiveness (PC20 of 1.16 mg/mL), supporting a diagnosis of asthma.13 The study was approved by the West Ethics Committee, West Glasgow Hospitals University NHS Trust, and each subject gave written informed consent.

Protocol
Asthmatic subjects attended the laboratory on two occasions: the first visit for consent, spirometry, and methacholine challenge testing as described for histamine by Cockcroft et al,14 and the second visit for sputum induction, within 1 week of the first visit. Nonasthmatic subjects did not undergo methacholine challenge testing. Smokers were not prohibited from smoking on the day of attendance, and nearly all reported that they had smoked that day, although we did not record the time of the last cigarette smoked. Sputum induction was performed using a modification of the method described by Pin et al.15 Briefly, after albuterol, 200 µg, was administered by metered-dose inhaler with a large-volume spacer, sputum induction was started using hypertonic (3%) saline solution administered via an ultrasonic nebulizer (Sonix 2000; Medix; Lutterworth, UK) over a period of 20 min. The subjects were encouraged to expectorate at any time throughout the procedure; in addition, inhalation was stopped every 5 min to allow expectoration, and to allow spirometry to be carried out. The sample was collected in a sterile container and was transferred to the laboratory on ice as soon as possible, in all cases in < 2 h. Protocol dictates that if FEV1 falls by > 20%, the procedure is discontinued, although no subjects in this study required discontinuation.

Laboratory Processing
All samples were processed without the laboratory staff being aware of the clinical information relating to the individual subject, and the procedure followed was similar to that described by Popov et al.16 Sputum samples were transferred to a Petri dish, and the volume and macroscopic characteristics of the whole sample were recorded. Sputum plugs were selected to minimize salivary contamination,17 and treated with 4x volume of fresh 0.1% dithiothreitol (DTT) [Sputolysin; Calbiochem-Novabiochem (UK) Ltd.; Nottingham, UK] in distilled H2O. Following incubation with DTT for 20 min, the DTT-treated samples were filtered through 50-µm mesh (R. Cadoch & Sons; London, UK) to remove residual mucus clumps, and a total cell count was made using a WBC counter (CBC5; Beckman-Coulter UK Ltd; High Wycombe, UK). An aliquot was removed, diluted to 106 cells/mL in phosphate-buffered saline solution, and cytocentrifuged (500 revolutions/min for 5 min). Differential cell counts were made from the resulting slides using Giemsa staining, and are expressed after exclusion of squamous epithelial cells that are taken to represent salivary contamination.17 The remaining sample was centrifuged (3,000 revolutions/min for 4 min), and the supernatant and cell pellet were separated and stored at - 70°C prior to assay. IL-8 was assayed using a commercially available assay kit (R&D Systems Europe; Abingdon, UK), with a sensitivity of < 10 pg/mL.

Analysis
Results are expressed as median and interquartile range (IQR) unless otherwise specified. Nonparametric statistics were used to compare cell counts and IL-8 values (Mann-Whitney U test) because data for cell counts and IL-8 are not normally distributed. Student’s t test used to compare demographic and spirometric data, and Spearman rank correlation for correlation. We found a greater range in total cell counts in the healthy nonsmoking group than we would have expected, and analysis of cell counts has therefore concentrated on cell proportions, rather than absolute numbers.


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Patients
There were no significant differences between the groups in terms of age or smoking history (Table 1 ). The mean (SD) resting prebronchodilator FEV1 percent predicted was lower in asthmatic smokers (83 [15]%), asthmatic nonsmokers (85 [16]%) and healthy smokers (91 [15]%) than the healthy nonsmokers (103.9 [14]%) [p < 0.05 in each case; Table 1 ]. All asthmatic patients had hyperreactive airways at screening, although one asthmatic smoker had a PC20 of 16 mg/mL at the study visit (geometric mean [range], 1.20 [0.03 to 4.6] mg/mL in nonsmokers and 1.15 [0.18 to 16] mg/mL in smokers).


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  		Table 1. Patient Characteristics and Demographic Factors*

 
Cell Counts
Median (IQR) total sputum cell counts were higher in asthmatic smokers (24.5 [19 to 29] x 106/mL) than healthy nonsmokers (9.8 [7.2 to 38.3] x 106/mL), healthy smokers (10.0 [3.0 to 19.3] x 106/mL), and asthmatic nonsmokers (13.0 [6 to 22] x 106/mL) [p < 0.05, p < 0.001, and p < 0.001, respectively]. Median (IQR) sputum eosinophil proportions were higher in both asthmatic smokers (0.4 [0 to 1]%) and nonsmokers (3.6 [1 to 6]%) than healthy subjects (0 in both healthy smokers and nonsmokers). Smoking was associated with a relative neutrophilia (median [IQR]) in both smoking groups compared to their controls, which was greater in absolute numbers in asthmatic smokers compared to nonasthmatic smokers: 9.1 (7 to 18) cells x 106/mL vs 3.6 (1.4 to 9.8) cells x 106/mL, respectively (p = 0.01). In asthmatic smokers, there was a weak but significant negative correlation between the sputum neutrophil proportion and pulmonary function as measured by FEV1 percent predicted (r = - 0.38, p < 0.05) that was not seen in other groups (Fig 1 , left, a).



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  		Figure 1. Relationships in asthmatic smokers between (left, a) sputum neutrophil proportion and FEV1 percent predicted, (middle, b) sputum IL-8 and smoking pack-years, and (right, c) sputum IL-8 and FEV1 percent predicted.

 
Sputum IL-8
The distribution of sputum IL-8 levels is shown in Table 2 . Sputum IL-8 was increased in asthmatic smokers compared with asthmatic nonsmokers (median [IQR], 945 [701 to 2,482] pg/mL vs 660 [486 to 1,045] pg/mL, respectively), and in healthy smokers compared with healthy nonsmokers (1,310 [770 to 3,300] pg/mL vs 561 [78 to 1,090] pg/mL, respectively). There was no significant difference in sputum IL-8 between asthmatic and healthy smokers. In healthy smokers, there was a positive correlation between absolute neutrophil count and sputum IL-8 (r = 0.52, p < 0.05). In asthmatic smokers, there was a positive correlation between sputum IL-8 and neutrophil proportion (r = 0.51, p < 0.01) that was not observed in the other patient groups, and between sputum IL-8 and smoking history in pack-years (r = 0.57, p < 0.005; Fig 1 , middle, b). There was a negative correlation in asthmatic smokers between sputum IL-8 and lung function, expressed as percent-predicted FEV1 (r = - 0.52, p < 0.005; Fig 1 , right, c). There were no significant relationships between sputum IL-8 and other cell numbers or proportions.


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  		Table 2. Total and Proportional Sputum Cell Counts, Sputum IL-8, and ECP in Asthmatic and Healthy Smokers and Nonsmokers*

 

   Discussion
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Studies examining airway inflammation in asthma have concentrated mainly on nonsmoking subjects, presumably to avoid the known effects of smoking confounding the pathogenic mechanisms under investigation, and there is therefore little direct information about the effect of smoking on asthmatic airway inflammation. We have demonstrated that cigarette smoking has an impact on asthmatic airway inflammation, with evidence of an increase in sputum WBC count, relative and absolute neutrophilia, and increased levels of the potent neutrophil chemoattractant IL-8 in smoking, compared to nonsmoking asthmatics. Sputum IL-8 was related to the cigarette-smoke exposure, and IL-8 levels and neutrophil proportion were both inversely related to the percent-predicted FEV1, suggesting an association between smoking, airway inflammation, and reduced pulmonary function. In these groups of relatively mild asthmatics (sufficiently mild for symptoms to be controlled with inhaled bronchodilators without additional inhaled steroids), there was mild sputum eosinophilia and increased sputum eosinophilic cationic protein (ECP) compared with nonasthmatic subjects, suggesting that the neutrophilic inflammation related to smoking may be additive to the underlying asthmatic airway inflammation.

Cigarette smoke is a complex mixture of > 4,000 chemical compounds, and smoking in nonasthmatic subjects is known to cause airway inflammation, with Roth et al7 demonstrating evidence of inflammatory cellular infiltration in bronchial biopsy; however, in the same study,7 BAL neutrophilia was only observed in a proportion of tobacco smokers compared with nonsmokers. Other workers10 have shown cigarette dose-dependent increases in BAL macrophages and neutrophils, along with the proinflammatory cytokines IL-1ß and IL-8, and have observed increased cell counts in BAL from smokers compared with nonsmokers. In nonasthmatics, contrary to expectations, we did not observe a significant difference in total cell counts comparing smokers and nonsmokers, although smokers had a relative sputum neutrophilia compared with nonsmokers. The reasons for this are not known, although the difference in neutrophil counts would suggest that this is not the result of confounding factors such as respiratory tract infection (subjects were excluded if overt infection was present), and may simply relate to natural variability or factors for which we did not control. It is not known if asthmatics are more sensitive than nonasthmatics to the detrimental effects of cigarette smoke in terms of airway inflammation or airway function, although it has been shown that improvements in airway function and plasma inflammatory markers in response to inhaled steroid therapy may be attenuated in asthmatic smokers compared to asthmatic nonsmokers.18 We found sputum neutrophilia in both asthmatic and nonasthmatic smokers, but absolute neutrophil numbers were greatest in smoking asthmatics; in asthmatic subjects, the separation between smokers and nonsmokers by neutrophil numbers is clearer than in nonasthmatic subjects despite similar cigarette exposure. In asthmatic smokers, we also found a significant negative relationship between sputum neutrophil proportion and FEV1, not present in the other groups, but which has previously been observed in patients with COPD,19 suggesting that the hypothesis that neutrophil products are pathogenic in the development of airflow obstruction in COPD may also be true in smoking asthmatics. In established COPD, both the sputum neutrophilia and the reduction in FEV1 is greater than that observed in our group of smoking asthmatics. We found a reduction in lung function in asthmatic smokers and nonsmokers compared to nonasthmatic nonsmokers, in keeping with epidemiologic observations.4 The mean eosinophil count in the nonsmoking asthmatics in this study was higher than that observed in the smoking asthmatics (mean, 3.6% vs 0.4%, respectively). The reasons for this difference are not known. In particular, we are not aware of any demonstrated suppressive effect of cigarette smoke on airway eosinophil numbers; indeed, the limited available evidence is to the contrary, with an animal study20 suggesting that cigarette smoke can induce eosinophilic airway inflammation. Further, epidemiologic data have shown21 increased peripheral eosinophilia in children of smoking parents, which was proportional to the number of cigarettes smoked by the parents. It is interesting to speculate that smokers may experience respiratory symptoms, either at a lesser degree of eosinophilic inflammation of the airways than nonsmokers, or alternatively via noneosinophilic mediated pathway(s).

IL-8 is a potent neutrophil chemoattractant and activator that can be released from macrophages, neutrophils,22 bronchial smooth-muscle cells,23 or airway epithelial cells.24 In an inflammatory milieu, neutrophils have the capacity to enforce their own recruitment by production of IL-8,25 and neutrophil elastase is a potent stimulus for IL-8 production by bronchial epithelial cells.26 The levels of sputum IL-8 that we found accord reasonably well with those observed by Keatings et al19 in asthmatics, control subjects, and nonasthmatic smokers using similar methodology; like Keatings et al,19 we did not find increased levels of IL-8 in induced sputum from asthmatic nonsmokers, in contrast to some studies27 28 using BAL fluid from asthmatics. It is clear that induced sputum does not sample the same compartment as BAL, and since induced sputum is richer in neutrophils and eosinophils and poorer in lymphocytes than BAL, it has been concluded that induced sputum samples mainly the larger airways.29 While induced-sputum induction is qualitatively different from BAL, it has advantages over BAL in that it is repeatable, noninvasive, offers higher density of cell recovery, and is not subject to the same unpredictable dilutional effects in the assessment of soluble mediators.30 Yamamoto et al31 described increased IL-8 in spontaneous sputum in established COPD, and found a relationship between IL-8 and lung function in patients with COPD. In the same study,31 increased sputum IL-8 was observed in a subgroup of smoking and ex-smoking asthmatics, but no relationship to lung function or sputum cell counts was described. We found a positive relationship in smoking asthmatics between sputum IL-8 and smoking history and between sputum IL-8 and sputum percent neutrophils, along with a negative relationship between sputum IL-8 and FEV1. Taken together with the cellular changes in smoking asthmatics, these data suggest that the differences in airway inflammation, IL-8 concentrations, and FEV1 in asthmatic smokers are related to their exposure to cigarette smoke; because these relationships were not observed in nonasthmatic smokers, we would speculate that asthmatic airways may be more sensitive at least to the proinflammatory effect of cigarette smoke. We did not, however, find a significant difference in sputum IL-8 between asthmatic smokers and nonasthmatic smokers, suggesting that the mechanism for this difference may depend on a number of factors, not simply on IL-8 concentrations alone. We conclude that asthmatic airway inflammation cannot be considered uniform between smokers and nonsmokers, and that there is evidence of different cellular and cytokine activation in induced sputum from smoking compared with nonsmoking asthmatics.

Airway inflammation in asthma is characteristically steroid responsive, with inhaled or oral steroids resulting in reduction in both symptoms and airway inflammation as measured by inflammatory cells (principally eosinophils) and markers of inflammation.30 32 We have shown that cigarette smoking in asthmatics promotes neutrophilic airway inflammation, with increased sputum IL-8, but the effect of inhaled steroids on sputum cell differential in asthmatic smokers has not yet been determined.


   Footnotes
 
Abbreviations: DTT = dithiothreitol; ECP = eosinophilic cationic protein; IL = interleukin; IQR = interquartile range; PC20 = provocative concentration of methacholine causing a 20% fall in FEV1

Dr. Chalmers was Chest Heart and Stroke Scotland Research Fellow, and Ms. Thomson and Dr. Little were funded by grants from the Scottish Home and Health Department, and the National Asthma Campaign, respectively.

Received for publication February 22, 2001. Accepted for publication June 19, 2001.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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Is the neutrophil the key effector cell in severe asthma?
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Histone acetylation and deacetylation: importance in inflammatory lung diseases
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Asthma and cigarette smoking
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Glucocorticoids: Effects on Gene Transcription
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Treatment of Nasal Inflammation Decreases the Ability of Subjects with Asthma to Condition Inspired Air
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T Sjaheim, T S Halstensen, M B Lund, O Bjortuft, P A Drablos, D Malterud, and J Kongerud
Airway inflammation in aluminium potroom asthma
Occup. Environ. Med., September 1, 2004; 61(9): 779 - 785.
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P. G Gibson
Smokers and ex-smokers with chronic stable asthma did not respond to high dose oral corticosteroids
Evid. Based Med., July 1, 2004; 9(4): 115 - 115.
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F. L. M. Ricciardolo, A. Di Stefano, N. C. Thomson, R. Chaudhuri, and E. Livingston
Corticosteroid Resistance in Smokers with Asthma
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Short-Term Smoke Exposure Attenuates Ovalbumin-Induced Airway Inflammation in Allergic Mice
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B.W.M. Willemse, D.S. Postma, W. Timens, and N.H.T. ten Hacken
The impact of smoking cessation on respiratory symptoms, lung function, airway hyperresponsiveness and inflammation
Eur. Respir. J., March 1, 2004; 23(3): 464 - 476.
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E. H. Bel
Smoking: A Neglected Cause of Glucocorticoid Resistance in Asthma
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Cigarette Smoking Impairs the Therapeutic Response to Oral Corticosteroids in Chronic Asthma
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Is sputum eosinophilia a good or poor predictor of benefit from inhaled corticosteroid therapy in asthma?
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