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Background: Most patients with mild to severe chronic obstructive pulmonary disease (COPD) experience exacerbations, which are also associated with increased healthcare costs. Despite limited evidence of antibiotics' benefits for exacerbations in outpatients, antibiotics are frequently prescribed. The aim of this study was to investigate whether doxycycline added to prednisolone is cost-effective compared to placebo plus prednisolone for the treatment of COPD acute exacerbations.Methods: An economic evaluation from the societal perspective was performed alongside a 2-year randomised trial in 301 COPD patients in the Netherlands. The primary outcome was cost per quality-adjusted life year (QALY). The secondary outcome was cost per exacerbation prevented. Healthcare utilisation and loss of productivity were measured using retrospective questionnaires and clinical report forms. Missing data were imputed using multiple imputations by chained equations. Bootstrapping was employed to estimate statistical uncertainty surrounding cost-effectiveness outcomes. A sensitivity analysis from the healthcare perspective was performed.Results: On average, costs in the doxycycline group were €898 higher than in the placebo group [95% confidence interval (CI) - 2617 to 4409] for the 2 years of follow-up. QALY values were higher in the doxycycline group (0.03; 95% CI - 0.00 to 0.06), but patients in this group suffered 0.01 more exacerbations than patients in the placebo group (95% CI - 0.14 to 0.11). Cost-effectiveness acceptability curves showed that the probability of doxycycline being cost-effective compared to placebo was 61% and 43% at a willingness-to-pay threshold of €34,000 per QALY and per exacerbation avoided, respectively. The sensitivity analysis showed similar results from the healthcare system perspective.Conclusions: In patients with mild to severe COPD treated for exacerbations in an outpatient setting, doxycycline added to prednisolone is not cost-effective compared to prednisolone plus placebo over a 2-year period. [ABSTRACT FROM AUTHOR]

Background: The decline in lung function can be reduced by long-term inhaled corticosteroid (ICS) treatment in subsets of patients with chronic obstructive pulmonary disease (COPD). We aimed to identify which clinical, physiological and non-invasive inflammatory characteristics predict the benefits of ICS on lung function decline in COPD. Methods: Analysis was performed in 50 steroid-naive compliant patients with moderate to severe COPD (postbronchodilator forced expiratory volume in one second (FEV1), 30–80% of predicted, compatible with GOLD stages II-III), age 45–75 years, >10 packyears smoking and without asthma. Patients were treated with fluticasone propionate (500 μg bid) or placebo for 2.5 years. Postbronchodilator FEV1, dyspnea and health status were measured every 3 months; lung volumes, airway hyperresponsiveness (PC20), and induced sputum at 0, 6 and 30 months. A linear mixed effect model was used for analysis of this hypothesis generating study. Results: Significant predictors of attenuated FEV1-decline by fluticasone treatment compared to placebo were: fewer packyears smoking, preserved diffusion capacity, limited hyperinflation and lower inflammatory cell counts in induced sputum (p<0.04). Conclusions: Long-term benefits of ICS on lung function decline in patients with moderate-to-severe COPD are most pronounced in patients with fewer packyears, and less severe emphysema and inflammation. These data generate novel hypotheses on phenotype-driven therapy in COPD. Trial Registration: ClinicalTrials.gov [ABSTRACT FROM AUTHOR]

The article discusses a study which examined whether withdrawal of inhaled corticosteroid (ICS) treatment induces a relapse of forced expiratory volume in one second (FEV1) in chronic obstructive pulmonary disease (COPD) patients. Topics discussed include the findings which suggest that ICS cessation after 30 months in COPD can worsen lung function decline, airway hyperresponsiveness (AHR) and quality of life (QOL).

Background: Inhaled corticosteroids (ICS) reduce exacerbation rates and improve health status but can increase the risk of pneumonia in COPD. The GLUCOLD study, investigating patients with mild-to-moderate COPD, has shown that long-term (2.5-year) ICS therapy induces anti-inflammatory effects. The literature suggests that cigarette smoking causes ICS insensitivity. The aim of this study is to compare anti-inflammatory effects of ICS in persistent smokers and persistent ex-smokers in a post-hoc analysis of the GLUCOLD study. Methods: Persistent smokers (n = 41) and persistent ex-smokers (n = 31) from the GLUCOLD cohort were investigated. Effects of ICS treatment compared with placebo were estimated by analysing changes in lung function, hyperresponsiveness, and inflammatory cells in sputum and bronchial biopsies during short-term (0–6 months) and long-term (6–30 months) treatment using multiple regression analyses. Results: Bronchial mast cells were reduced by short-term and long-term ICS treatment in both smokers and ex-smokers. In contrast, CD3+, CD4+, and CD8+ cells were reduced by short-term ICS treatment in smokers only. In addition, sputum neutrophils and lymphocytes, and bronchial CD8+ cells were reduced after long-term treatment in ex-smokers only. No significant interactions existed between smoking and ICS treatment. Conclusion: Even in the presence of smoking, long-term ICS treatment may lead to anti-inflammatory effects in the lung. Some anti-inflammatory ICS effects are comparable in smokers and ex-smokers with COPD, other effects are cell-specific. The clinical relevance of these findings, however, are uncertain. [ABSTRACT FROM AUTHOR]

Introduction: Classification of COPD is currently based on the presence and severity of airways obstruction. However, this may not fully reflect the phenotypic heterogeneity of COPD in the (ex-) smoking community. We hypothesized that factor analysis followed by cluster analysis of functional, clinical, radiological and exhaled breath metabolomic features identifies subphenotypes of COPD in a community-based population of heavy (ex-) smokers. Methods: Adults between 50-75 years with a smoking history of at least 15 pack-years derived from a random population-based survey as part of the NELSON study underwent detailed assessment of pulmonary function, chest CT scanning, questionnaires and exhaled breath molecular profiling using an electronic nose. Factor and cluster analyses were performed on the subgroup of subjects fulfilling the GOLD criteria for COPD (post-BD FEV1/FVC < 0.70). Results: Three hundred subjects were recruited, of which 157 fulfilled the criteria for COPD and were included in the factor and cluster analysis. Four clusters were identified: cluster 1 ( n = 35; 22%): mild COPD, limited symptoms and good quality of life. Cluster 2 ( n = 48; 31%): low lung function, combined emphysema and chronic bronchitis and a distinct breath molecular profile. Cluster 3 ( n = 60; 38%): emphysema predominant COPD with preserved lung function. Cluster 4 ( n = 14; 9%): highly symptomatic COPD with mildly impaired lung function. In a leave-one-out validation analysis an accuracy of 97.4% was reached. Conclusions: This unbiased taxonomy for mild to moderate COPD reinforces clusters found in previous studies and thereby allows better phenotyping of COPD in the general (ex-) smoking population. [ABSTRACT FROM AUTHOR]

Background: Eosinophilic airway inflammation has successfully been used to tailor anti-inflammatory therapy in chronic obstructive pulmonary disease (COPD). Airway hyperresponsiveness (AHR) by indirect challenges is associated with airway inflammation. We hypothesized that AHR to inhaled mannitol captures eosinophilia in induced sputum in COPD. Methods: Twenty-eight patients (age 58 ± 7.8 yr, packyears 40 ± 15.5, post-bronchodilator FEV1 77 ± 14.0% predicted, no inhaled steroids =4 wks) with mild-moderate COPD (GOLD I-II) completed two randomized visits with hypertonic saline-induced sputum and mannitol challenge (including sputum collection). AHR to mannitol was expressed as response-dose-ratio (RDR) and related to cell counts, ECP, MPO and IL-8 levels in sputum. Results: There was a positive correlation between RDR to mannitol and eosinophil numbers (r = 0.47, p = 0.03) and level of IL-8 (r = 0.46, p = 0.04) in hypertonic saline-induced sputum. Furthermore, significant correlations were found between RDR and eosinophil numbers (r = 0.71, p = 0.001), level of ECP (r = 0.72, p = 0.001), IL-8 (r = 0.57, p = 0.015) and MPO (r = 0.64, p = 0.007) in sputum collected after mannitol challenge. ROC-curves showed 60% sensitivity and 100% specificity of RDR for >2.5% eosinophils in mannitol-induced sputum. Conclusions: In mild-moderate COPD mannitol hyperresponsiveness is associated with biomarkers of airway inflammation. The high specificity of mannitol challenge suggests that the test is particularly suitable to exclude eosinophilic airways inflammation, which may facilitate individualized treatment in COPD. Trial registration: Netherlands Trial Register (NTR): NTR1283 [ABSTRACT FROM AUTHOR]

Asthma and COPD are chronic respiratory diseases that fluctuate widely with regard to clinical symptoms and airway obstruction, complicating treatment and prediction of exacerbations. Time series of respiratory impedance obtained by the forced oscillation technique are a convenient tool to study the respiratory system with high temporal resolution. In previous studies it was suggested that power-law-like fluctuations exist also in the healthy lung and that respiratory system impedance variability differs in asthma. In this study we elucidate such differences in a population of well-characterized subjects with asthma (n = 13, GINA 1+2), COPD (n = 12, GOLD I+II), and controls (n = 10) from time series at single frequency (12 min, f = 8 Hz). Maximum likelihood estimation did not rule out power-law behavior, accepting the null hypothesis in 17/35 cases (P > 0.05) and with significant differences in exponents for COPD (P < 0.03). Detrended fluctuation analysis exhibited scaling exponents close to 0.5, indicating few correlations, with no differences between groups (P > 0.14). In a second approach, we considered asthma and COPD as dynamic diseases, corresponding to changes of unknown parameters in a deterministic system. The similarity in shape between the combined probability distributions of normalized resistance and reactance was quantified by Wasserstein distances and reliably distinguished the two diseases (cross-validated predictive accuracy 0.80; sensitivity 0.83, specificity 0.77 for COPD). Wasserstein distances between 3+3 dimensional phase space reconstructions resulted in marginally better classification (accuracy 0.84, sensitivity 0.83, specificity 0.85). These latter findings suggest that the dynamics of respiratory impedance contain valuable information for the diagnosis and monitoring of patients with asthma and COPD, whereas the value of the stochastic approach is not clear presently. [ABSTRACT FROM AUTHOR]

The article proposes an integrative systems biology research strategy designed to provide a better understanding of chronic inflammatory pulmonary diseases such as asthma and chronic obstructive pulmonary disease. The strategy aims to identify the functional and regulatory factors that play major roles in respiratory pathophysiology. It relies on global genome, transcriptome, proteome and metabolome data collected from patient cohorts.

Background: Inhaled corticosteroids (ICSs) and long-acting β2- agonists (LABAs) are used to treat moderate to severe chronic obstructive pulmonary disease (COPD). Objective: To determine whether long-term ICS therapy, with and without LABAs, reduces inflammation and improves pulmonary function in COPD. Design: Randomized, placebo-controlled trial. (ClinicalTrials.gov registration number: NCT00158847) Setting: 2 university medical centers in The Netherlands. Patients: 114 steroid-naive current or former smokers with moderate to severe COPD. Measurements: Cell counts in bronchial biopsies and sputum (primary outcome); methacholine responsiveness at baseline, 6, and 30 months; and clinical outcomes every 3 months. Intervention: Random assignment by minimization method to receive fluticasone propionate, 500 μg twice daily, for 6 months (n = 31) or 30 months (n = 26); fluticasone, 500 μg twice daily, and salmeterol, 50 μg twice daily, for 30 months (single inhaler; n = 28); or placebo twice daily (n = 29). Results: 101 patients were greater than 70% adherent to therapy. Fluticasone therapy decreased counts of mucosal CD3μ cells (-55% [95% CI, -74% to -22%]; P = 0.004), CD4μ cells (-78% [CI, -88% to 60%]; P = 0.001), CD8μ cells (-57% [CI, -77% to -18%]; P = 0.010), and mast cells (-38% [CI, -60% to -2%]; P = 0.039) and reduced hyperresponsiveness (P = 0.036) versus placebo at 6 months, with effects maintained after 30 months. Fluticasone therapy for 30 months reduced mast cell count and increased eosinophil count and percentage of intact epithelium, with accompanying reductions in sputum neutrophil, macrophage, and lymphocyte counts and improvements in FEV1 decline, dyspnea, and quality of life. Reductions in inflammatory cells correlated with clinical improvements. Discontinuing fluticasone therapy at 6 months increased counts of CD3+ cells (120% [CI, 24% to 289%]; P = 0.007), mast cells (218% [CI, 99% to 407%]; P < 0.001), and plasma cells (118% [CI, 9% to 336%]; P = 0.028) and worsened clinical outcome. Adding salmeterol improved FEV1 level. Limitations: The study was not designed to evaluate clinical outcomes. Measurement of primary outcome was not available for 24% of patients at 30 months. Conclusion: ICS therapy decreases inflammation and can attenuate decline in lung function in steroid-naive patients with moderate to severe COPD. Adding LABAs does not enhance these effects. Primary Funding Source: Netherlands Organization for Scientific Research, Netherlands Asthma Foundation, GlaxoSmithKline of The Netherlands, University Medical Center Groningen, and Leiden University Medical Center. [ABSTRACT FROM AUTHOR]

Deep inspiration temporarily reduces induced airways obstruction in healthy subjects. This bronchodilatory effect of deep inspiration is impaired in asthma. Passive machine-assisted lung inflation may augment bronchodilation compared with an active deep inspiration in patients with asthma by either opening closed airways or by reducing fluid flux across the airway wall during deep inspiration, and thereby increasing the tethering forces on the airway wall. We recruited 24 patients with asthma [18-46 yr old, forced expiratory volume in 1 s (FEV1) > 70% predicted; provocative concentration of methacholine inducing a 20% fall in FEV1 (PC20) < 8 mg/ml], with either an impaired (n = 12) or an intact (n = 12) bronchodilatory response to deep inspiration. Two methacholine challenges were performed on separate days. At a 50% increase in respiratory resistance (forced oscillation technique at 8 Hz), the change in resistance by a positive-pressure inflation (computer-driven syringe) or an active deep inspiration was measured in randomized order. The reduction in resistance by positive-pressure inflation was significantly greater than by active deep inspiration in the impaired deep inspiration response group (mean change ± SE: -0.6 ± 0.1 vs. -0.03 ± 0.2 cmH2O•1-1•s,P = 0.002). No significant difference was found between positive-pressure inflation and active deep inspiration in the intact deep inspiration response group(-0.6 ± 0.2 vs. -1.0 ± 0.3 cmH2O•1-1s,P = 0.18). Positive-pressure inflation of the lungs can significantly enhance deep inspiration-induced bronchodilation in patients with asthma. [ABSTRACT FROM AUTHOR]

Background: Roflumilast is a targeted oral once-daily administered phosphodiesterase 4 (PDE4) inhibitor with clinical efficacy in chronic obstructive pulmonary disease (COPD). Results from in vitro studies with roflumilast indicate that it has anti-inflammatory properties that may be applicable for the treatment of COPD. Methods: In a crossover study, 38 patients with COPD (mean (SD) age 63.1(7.0) years, post-bronchodilator forced expiratory volume in 1 s (FEV1) 61 .0 (1 2.6)% predicted) received 500 μg roflumilast or placebo once daily for 4 weeks. Induced sputum samples were collected before and after 2 and 4 weeks of treatment. Differential and absolute cell counts were determined in whole sputum samples. Markers of inflammation were determined in sputum supernatants and blood. Spirometry was performed weekly. Results: Roflumilast significantly reduced the absolute number of neutrophils and eosinophils/g sputum compared with placebo by 35.5% (95% CI 15.6% to 50.7%; p = 0.002) and 50.0% (95% CI 26.8% to 65.8%; p<0.001), respectively. The relative proportion of sputum neutrophils and easinophils was not affected by treatment (p<0.05). Levels of soluble interleukin-8, neutrophil elastase, eosinophil cationic protein and α2- macroglobulin in sputum and the release of tumour necrosis factor α from blood cells were significantly reduced by roflumilast compared with placebo treatment (p<0.05 for all). Post-bronchodilator FE1 improved significantly during roflumilast compared with placebo treatment with a mean difference between treatments of 68.7 ml (95% CI 12.9 to 124.5; p = 0.018). Conclusion: PDE4 inhibition by roflumilast treatment for 4 weeks reduced the number of neutrophils and eosinophils, as well as soluble markers of neutrophilic and eosinophilic inflammatory activity in induced sputum samples of patients with COPD. This anti-inflammatory effect may in part explain the concomitant improvement in post-bronchodilator FEV1. [ABSTRACT FROM AUTHOR]

Background: Exhaled breath contains thousands of volatile organic compounds (VOCs) that could serve as biomarkers of lung disease. Electronic noses can distinguish VOC mixtures by pattern recognition. Objective: We hypothesized that an electronic nose can discriminate exhaled air of patients with asthma from healthy controls, and between patients with different disease severities. Methods: Ten young patients with mild asthma (25.1 ± 5.9 years; FEV1, 99.9 ± 7.7% predicted), 10 young controls (26.8 ± 6.4 years; FEV1, 101.9 ± 10.3), 10 older patients with severe asthma (49.5 ± 12.0 years; FEV1, 62.3 ± 23.6), and 10 older controls (57.3 ± 7.1 years; FEV1, 108.3 ± 14.7) joined a cross-sectional study with duplicate sampling of exhaled breath with an interval of 2 to 5 minutes. Subjects inspired VOC-filtered air by tidal breathing for 5 minutes, and a single expiratory vital capacity was collected into a Tedlar bag that was sampled by electronic nose (Cyranose 320) within 10 minutes. Smellprints were analyzed by linear discriminant analysis on principal component reduction. Cross-validation values (CVVs) were calculated. Results: Smellprints of patients with mild asthma were fully separated from young controls (CVV, 100%; Mahalanobis distance [M-distance], 5.32), and patients with severe asthma could be distinguished from old controls (CVV, 90%; M-distance, 2.77). Patients with mild and severe asthma could be less well discriminated (CVV, 65%; M-distance, 1.23), whereas the 2 control groups were indistinguishable (CVV, 50%; M-distance, 1.56). The duplicate samples replicated these results. Conclusion: An electronic nose can discriminate exhaled breath of patients with asthma from controls but is less accurate in distinguishing asthma severities. Clinical implication: These findings warrant validation of electronic noses in diagnosing newly presented patients with asthma. [Copyright &y& Elsevier]

The term severe refractory asthma (SRA) in adults applies to patients who remain difficult to control despite extensive re-evaluation of diagnosis and management following an observational period of at least 6 months by a specialist. Factors that influence asthma control should be recognized and adequately addressed prior to confirming the diagnosis of SRA. This report presents statements according to the literature defining SRA in order address the important questions. Phenotyping SRA will improve our understanding of mechanisms, natural history, and prognosis. Female gender, obesity, and smoking are associated with SRA. Atopy is less frequent in SRA, but occupational sensitizers are common inducers of new-onset SRA. Viruses contribute to severe exacerbations and can persist in the airways for long periods. Inflammatory cells are in the airways of the majority of patients with SRA and persist despite steroid therapy. The TH2 immune process alone is inadequate to explain SRA. Reduced responsiveness to corticosteroids is common, and epithelial cell and smooth muscle abnormalities are found, contributing to airway narrowing. Large and small airway wall thickening is observed, but parenchymal abnormalities may influence airway limitation. Inhaled corticosteroids and bronchodilators are the mainstay of treatment, but patients with SRA remain uncontrolled, indicating a need for new therapies. [Copyright &y& Elsevier]

The article discusses a study which examined whether uneven ventilation and airway closure are associated with specific markers of airway inflammation as obtained by bronchial biopsies, bronchoalveolar lavage (BAL) and induced sputum in chronic obstructive pulmonary disease patients. The results of the single-breath N2 test are associated with neutrophilic inflammation in bronchial biopsies and BAL.

The article presents information on a study focusing on asthmatics whose conditions are being clinically well-controlled with inhaled steroid therapy. Asthma is a chronic inflammatory disorder of the airways. Airway inflammation can persist despite inhaled corticosteroid treatment, although the particular treatment has been shown to improve airway responses to deep inspiration in patients with asthma. It was found that residual inflammation impairs airway mechanics in asthma patients.

Background: Chronic obstructive pulmonary disease (COPD) is characterized by irreversible airflow limitation and airway inflammation, accompanied by decreased health status. It is still unknown which factors are responsible for the impaired health status in COPD. We postulated that airway inflammation negatively contributes to health status in COPD. Methods: In 114 COPD patients (99 male, age: 62 ± 8 yr, 41 [31-55] pack-years, no inhaled or oral corticosteroids, postbronchodilator FEV1: 63 ± 9% pred, FEV1/IVC: 48 ± 9%) we obtained induced sputum and measured health status (St. George's respiratory questionnaire (SGRQ)), postbronchodilator FEV1, hyperinflation (RV/TLC), and airway hyperresponsiveness to methacholine (PC20). Sputum was induced by hypertonic saline and differential cell counts were obtained in 102 patients. Results: Univariate analysis showed that SGRQ total and symptom score were positively associated with % sputum macrophages (r = 0.20, p = 0.05; and r = 0.20, p = 0.04, respectively). Multiple regression analysis confirmed these relationships, providing significant contributions of % sputum macrophages (B = 0.25, p = 0.021) and RV/TLC (B = 0.60, p = 0.002) to SGRQ total score. Furthermore, SGRQ symptom score was associated with % sputum macrophages (B = 0.30, p = 0.03) and RV/TLC (B = 0.48, p = 0.044), whilst SGRQ activity score was associated with % sputum macrophages (B = 0.46, p = 0.002), RV/TLC (B = 0.61, p = 0.015), and PC20 (B = -9.3, p = 0.024). Current smoking and FEV1 were not significantly associated with health status in the multiple regression analysis. Conclusion: We conclude that worse health status in COPD patients is associated with higher inflammatory cell counts in induced sputum. Our findings suggest that airway inflammation and hyperinflation independently contribute to impaired health status in COPD. This may provide a rationale for anti-inflammatory therapy in this disease. [ABSTRACT FROM AUTHOR]

Background: The mechanisms leading to death from asthma are not completely understood. Recent studies suggest the involvement of the anaphylatoxins C3a and C5a, generated during complement activation, and their receptors C3aR and C5aR in the pathogenesis of asthma. Objective: The aim of our study was to investigate the expression of C3aR and C5aR in fatal asthma. Methods: We analyzed lung tissue from 14 subjects who died of asthma (fatal asthma; FA) and 14 subjects who died of nonpulmonary causes (controls) and bronchial biopsy specimens from 16 subjects with mild intermittent asthma (MIA). C3aR and C5aR expression was evaluated by immunohistochemistry, and a semiquantitative analysis of the intensity of staining was performed according to a visual analogue scale (score, 0-3). Results: C3aR was expressed on airway epithelium, smooth muscle, submucosal, and parenchymal vessels. C5aR was expressed on myeloid cells infiltrating the submucosa and on airway epithelium. Statistical analysis demonstrated higher expression of C3aR on submucosal vessels in FA compared with controls and MIA (median [minimum-maximum], controls, 0.24 [0-1.48]; MIA, 0.0 [0-1.00]; FA, 1.56 [0.13-3]; P =.002). C3aR was also increased on parenchymal vessels in FA (controls, 0.56 [0-2.00]; FA, 1.81 [0.5-3]; P =.0004). C5aR expression on airway epithelium was increased in FA compared with controls and MIA (controls, 1.25 [0.25-3]; MIA, 1.00 [0-2.00]; FA, 3.00 [1.13-3.00]; P =.001). Conclusion: The results of our study suggest a role of complement in FA. [Copyright &y& Elsevier]

Abstract: Non-adrenergic non-cholinergic (NANC) nerves release bronchoactive tachykinins such as substance P (SP) and neurokinin A (NKA) that can induce features of asthma. The airway response to NKA in humans closely resembles that of methacholine (M). Hence, we investigated the relationship between airway responsiveness to NKA and M in subjects with asthma. To this end, we analyzed baseline data of 27 subjects with mild persistent asthma (20F/7M) 19–46 y; FEV1 81–136% pred.; PC20FEV1 (M)&#60;80μmol/mL) participating in a proof-of-concept study. All subjects were non-smokers and asthma was controlled by on demand short-acting β2-agonists only. Dose-response curves to M (0.15–80μmol/mL) and NKA (3.4 (10−3)–0.88μmol/mL) were performed on two separate days, and airway response was measured by FEV1 until a ≥20% fall from baseline (PC20FEV1). Twenty-two subjects reached a PC20FEV1 on both occasions. The PC20FEV1 values of both agonists correlated significantly (Spearman''s r=−0.721; p=0.0002), and the relationship was given by 10log(PC20FEV1(NKA))=−1.36+ (0.60×10log(PC20FEV1(M)). We have demonstrated a significant relationship between airway responsiveness to NKA and methacholine in asthma. This suggests that both agonists may share common final pathways in causing bronchoconstriction in patients with mild persistent asthma. Based on our data and previous studies in asthma, it can be hypothesized that this direct NKA-induced bronchoconstrictor response may be mediated by predominant stimulation of the tachykinin NK-2 receptors on airway smooth muscle cells. [Copyright &y& Elsevier]