Smoking is the main risk factor in the development of chronic obstructive pulmonary disease (COPD), and smoking cessation is the only effective treatment for avoiding or reducing the progression of this disease.Despite the fact that smoking cessation is a very important health issue, information about the underlying mechanisms of the effects of smoking cessation on the lungs is surprisingly scarce. It is likely that the reversibility of smoke-induced changes differs between smokers without chronic symptoms, smokers with nonobstructive chronic bronchitis and smokers with COPD. This review describes how these three groups differ regarding the effects of smoking cessation on respiratory symptoms, lung function (forced expiratory volume in one second), airway hyperresponsiveness, and pathological and inflammatory changes in the lung.Smoking cessation clearly improves respiratory symptoms and bronchial hyperresponsiveness, and prevents excessive decline in lung function in all three groups.Data from well-designed studies are lacking regarding the effects on inflammation and remodelling, and the few available studies show contradictory results. In chronic obstructive pulmonary disease, a few histopathological studies suggest that airway inflammation persists in exsmokers. Nevertheless, many studies have shown that smoking cessation improves the accelerated decline in forced expiratory volume in one second, which strongly indicates that important inflammatory and/or remodelling processes are positively affected.

We found no differences in asthma severity between obese and nonobese asthmatics. Interestingly, obese patients demonstrated more neutrophils in sputum and blood than nonobese patients. The smaller improvement in FEV(1) and sputum eosinophils suggests a worse corticosteroid treatment response in obese asthmatics.

A subset of asthma patients suffer from glucocorticoid (GC) insensitivity. T-helper cell type 17 cells have an emerging role in GC insensitivity, although the mechanisms are still poorly understood.We investigated whether interleukin (IL)-17A induces GC insensitivity in airway epithelium by studying its effects on responsiveness of tumour necrosis factor (TNF)-a-induced IL-8 production to budesonide in human bronchial epithelial 16HBE cells. We unravelled the underlying mechanism by the use of specific pathway inhibitors, reporter and overexpression constructs and a histone deacetylase (HDAC) activity assay.We demonstrated that IL-17A-induced IL-8 production is normally sensitive to GCs, while IL-17A pre-treatment significantly reduced the sensitivity of TNF-a-induced IL-8 production to budesonide. IL-17A activated the p38, extracellular signal-related kinase (ERK) and phosphoinositide-3-kinase (PI3K) pathways, and the latter appeared to be involved in IL-17A-induced GC insensitivity. Furthermore, IL-17A reduced HDAC activity, and overexpression of HDAC2 reversed IL-17A-induced GC insensitivity. In contrast, IL-17A did not affect budesonide-induced transcriptional activity of the GC receptor, suggesting that IL-17A does not impair the actions of the ligated GC receptor.In conclusion, we have shown for the first time that IL-17A induces GC insensitivity in airway epithelium, which is probably mediated by PI3K activation and subsequent reduction of HDAC2 activity. Thus, blockade of IL-17A or downstream signalling molecule PI3K may offer new strategies for therapeutic intervention in GC-insensitive asthma.

To cite this article: van den Berge M, ten Hacken NHT, van der Wiel E, Postma DS. Treatment of the bronchial tree from beginning to end: targeting small airway inflammation in asthma. Allergy 2013; 68: 16-26.

Small airways are an important site of inflammation and obstruction in asthma, which contributes to the severity of airway hyperresponsiveness (AHR) that is usually measured by nebulisation of large-particle stimuli. We investigated whether small and large particle sizes of aerosolised adenosine monophospate (AMP) provoke similar severity of AHR. Additionally, effects of the small-particle inhaled corticosteroid (ICS) ciclesonide and large-particle ICS fluticasone on AHR to large-and small-particle size AMP were assessed.After a 4-week run-in period using open-label fluticasone (100 mg b.i.d.), 37 mild-to-moderate asthmatics underwent provocations with standard-size (3.7 mm), large-particle (9.9 mm) and smallparticle (1.06 mm) AMP. Subjects received 4-week ciclesonide (160 mg s.i.d.) or fluticasone (100 mg b.i.d.) treatment (double-blind and double-dummy) followed by large-and small-particle AMP provocation.Small-particle AMP induced a 20% decrease in forced expiratory volume in 1 s (FEV1) at a significantly higher dose than large-particle AMP. Ciclesonide and fluticasone had comparable effects on AMP provocations. Not all subjects reached the provocative concentration causing a 20% fall in FEV1 (PC20) at the highest AMP dose. In those who did, ciclesonide improved smallparticle AMP PC20 by 1.74 doubling doses (DD) (p50.03), whereas fluticasone did not. Conversely, fluticasone improved large-particle AMP PC20 significantly (1.32 DD; p50.03), whereas ciclesonide did not.Small-particle AMP provocation appears to be a promising tool to assess changes in small airway inflammation. Future adjustments are necessary taking into account the very small particle size used, with large exhaled fractions. In asthmatics reaching a PC20 with small-and largeparticle AMP provocations, ciclesonide improves hyperresponsiveness to small particle size AMP, and fluticasone to large particle size. This warrants further research to target provocations and treatment to specific airway sizes.

Nitric oxide in exhaled air is thought to reflect airway inflammation. No data have been reported so far on circadian changes in NO in subjects with nocturnal asthma. To determine whether exhaled NO shows a circadian rhythm inverse to the circadian rhythm in airway obstruction in subjects with nocturnal asthma, we conducted a study involving six healthy controls, eight individuals without nocturnal asthma (4-h to 16-h variation in peak expiratory flow [PEF] <= 15%), and six individuals with nocturnal asthma (4-h to 16-h PEF variation > 15%). Smoking, use of corticosteroids, and recent respiratory infections were excluded. NO concentrations were measured at 12, 16, 20, and 24 h, and at 4, 8, and 12 h of the next day, using the single-breath method. At the same times, FEV1 and PEF were also measured. Mean NO concentrations were significantly higher in subjects with nocturnal asthma than in subjects without nocturnal asthma, and higher in both groups than in healthy controls at all time points. Mean exhaled NO levels over 24 h correlated with the 4-h to 16-h variation in PEF (r = 0.61, p < 0.01). Exhaled NO did not show a significant circadian variation in any of the three groups as assessed with cosinor analysis, in contrast to the FEV1 in both asthma groups (p < 0.05). At 4 h, mean +/- SD NO levels were higher than at 16 h in subjects with nocturnal asthma; at 50 +/- 20 ppb versus 42 +/- 15 ppb (p < 0.05); other measurements at all time points were similar. Differences in NO and FEV1 from 4 h to 16 h did not correlate with one another. We conclude that subjects with nocturnal asthma exhale NO at higher levels both at night and during the day, which may reflect more severe diurnal airway-wall inflammation. A circadian rhythm in exhaled NO was not observed. NO levels did not correspond to the circadian rhythm in airway obstruction. The small increase in NO at 4 h may indicate an aspect of inflammation, but it is not associated with increased nocturnal airway obstruction.

BackgroundCOPD patients have a higher risk of pneumonia when treated with fluticasone propionate (FP) than with placebo, and a lower risk with budesonide (BUD). We hypothesized that BUD and FP differentially affect the mucosal barrier in response to viral infection and/or cigarette smoke.MethodsWe assessed protective effects of equivalent concentrations of BUD and FP on cytokine production and barrier function (electrical resistance) in human bronchial epithelial 16HBE cells and primary bronchial epithelial cells (PBECs) upon exposure to viral mimetic poly-(I:C) and/or cigarette smoke extract (CSE) or epidermal growth factor (EGF).ResultsBUD and FP were equally effective in suppressing poly-(I:C)- and/or CSE-induced IL-8 secretion in 16HBE and PBECs. Poly-(I:C) substantially decreased electrical resistance in 16HBE cells and both BUD and FP fully counteracted this effect. However, FP hardly affected 16HBE barrier dysfunction induced by CSE with/without poly-(I:C), whereas BUD (16 nM) provided full protection, an effect likely mediated by affecting EGFR-downstream target GSK-3β. Similarly, BUD, but not FP, significantly improved CSE-induced barrier dysfunction in PBECs. Finally, BUD, but not FP, exerted a modest but significant protective effect against Streptococcus Pneumoniae-induced barrier dysfunction, and BUD, but not FP, prevented cellular adhesion and/or internalization of these bacteria induced by poly-(I:C) in 16HBE.ConclusionsCollectively, both BUD and FP efficiently control epithelial pro-inflammatory responses and barrier function upon mimicry of viral infection. Of potential clinical relevance, BUD more effectively counteracted CSE-induced barrier dysfunction, reinforcing the epithelial barrier and potentially limiting access of pathogens upon smoking in vivo.

The presence of chronic bronchitis predicts a more rapid decline of forced expiratory volume in one second (FEV1) in patients with chronic obstructive pulmonary disease (COPD). The hallmark of COPD is airway inflammation. It was hypothesised that COPD patients with chronic bronchitis are characterised by a distinct inflammatory cell profile, as measured in bronchial biopsies and sputum.From 114 COPD patients (male/female ratio 99/15, mean¡SD age 62¡8 yrs, current smoking 63%, post-bronchodilator FEV1 63¡9% predicted, no steroids), with and without chronic bronchitis, inflammatory cell counts in bronchial biopsies and induced sputum were measured. Analysis was carried out by logistic regression.COPD patients with chronic bronchitis had lower eosinophil counts in biopsies and higher percentages of sputum eosinophils than patients without those symptoms, which remained after adjustment for smoking and sex. Patients with chronic bronchitis also showed higher percentages of macrophages and lower percentages of neutrophils in sputum, which could be explained by differences in smoking and sex.It was concluded that chronic bronchitis reflects an inflammatory sub-phenotype among patients with chronic obstructive pulmonary disease. The present results indicate a preferential distribution of eosinophils towards the airway lumen in patients with chronic bronchitis. This may have implications for anti-inflammatory treatment of chronic obstructive pulmonary disease patients with chronic bronchitis.