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Severe asthma accounts for a small number of asthmatics but represents a disproportionate cost to health care systems. The underlying mechanism in severe asthma remains unknown but several mechanisms are likely to be involved because of a very heterogeneous profile. We investigated the effects of a p38MAPK inhibitor in corticosteroid sensitivity in peripheral blood mononuclear cells (PBMCs) from severe asthmatics and the profile of its responders. Corticosteroid sensitivity was determined by measuring dexamethasone inhibition of CD3/28 and TNF-α induced IL-8 production in PBMCs by using ELISA. PBMCs from severe asthmatics were relatively less sensitive to dexamethasone (Dex) as compared to those of non-severe asthmatics and healthy volunteers. The IC(50) values of Dex negatively correlated with decreased glucocorticoid receptor (GR) nuclear translocation assessed using immunocytochemistry (r = -0.65; p<0.0005) and with decreased FEV(1) (% predicted) (r = 0.6; p<0.0005). A p38α/β inhibitor (SB203580) restored Dex-sensitivity in a subpopulation of severe asthma that was characterized by a defective GR nuclear translocation, clinically by lower FEV(1) and higher use of oral prednisolone. We also found that SB203580 partially inhibited GR phosphorylation at serine 226, resulting in increased GR nuclear translocation in IL-2/IL-4 treated corticosteroid insensitive U937s. p38MAPKα/β is involved in defective GR nuclear translocation due to phosphorylation at Ser226 and this will be a useful biomarker to identify responders to p38MAPKα/β inhibitor in the future.

To the Editor: The latest Global Initiative for Chronic Obstructive Lung Disease document recommends new treatment algorithms, with inhaled corticosteroid (ICS) use only in moderate to severely symptomatic patients with chronic obstructive pulmonary disease (COPD) with repeated exacerbations, where the emphasis is to review ICS use and to reduce ICS dosing (1). Conclusions Our data show for the first time, in low-risk patients with COPD, that a single low dose of inhaled budesonide/formoterol 400/12 mg is as effective as a high dose of budesonide 800 mg or budesonide/formoterol 800/24 mg in suppressing protein levels of a molecular marker of airway inflammation in sputum 2 hours after inhalation. Furthermore, this is associated with a significant increase of GR activity and improvement in lung function that is as effective or superior to double the dose of inhaled budesonide. [...]lowering a single dose of ICS and LABA in low-risk patients with COPD does not risk the loss of valuable cellular and biological anti-inflammatory activity and preserves lung function improvement.

Abstract Rationale and Objectives Patients with severe asthma have a poor therapeutic response to corticosteroid therapy, and corticosteroid responsiveness cannot be easily measured in these patients. We hypothesized that this poor response is associated with a reduced effect of corticosteroids to inhibit cytokine release from activated peripheral blood mononuclear cells (PBMCs). Methods Patients with severe asthma were defined by American Thoracic Society criteria. We compared the suppression of LPS-induced cytokine release (monocyte chemotactic protein-1 [MCP-1], macrophage inflammatory protein [MIP] 1α, RANTES, tumor necrosis factor α, interleukin 1β (IL-1β), IL-8, IFN-γ, IL-6, IL-10, and granulocyte-macrophage colony–stimulating factor [GM-CSF]) by dexamethasone from PBMCs of patients with severe asthma (n = 16), patients with nonsevere asthma (n = 19), and normal volunteers (n = 10). Results There was no difference in baseline spontaneous or stimulated release of these cytokines among groups. LPS-induced release of 10 cytokines was less suppressed by dexamethasone (10−6 M) in patients with severe asthma compared with patients with nonsevere asthma, with statistical significance achieved for IL-1β (p < 0.03), IL-8 (p < 0.03), and MIP-1α (p < 0.003), and borderline significance for IL-6 (p = 0.054). There was less difference between the two groups for dexamethasone at 10−8 M. Nuclear histone deacetylase (HDAC) and histone acetyltransferase activities were reduced in patients with severe asthma compared with patients with nonsevere asthma (p < 0.01). HDAC activity reduction correlated directly to the degree of steroid insensitivity of GM-CSF (r = 0.57, p < 0.01) and IFN-γ (r = 0.56, p < 0.05) release. Reduction in histone acetyltransferase activity related to corticosteroid use rather than asthma severity. Conclusions Patients with severe asthma have diminished corticosteroid sensitivity of PBMCs when compared with patients with nonsevere asthma, associated with a reduction in HDAC activity that parallels the impaired corticosteroid sensitivity.

Background Our aim was to investigate total and regional lung delivery of salbutamol in subjects with idiopathic pulmonary fibrosis (IPF). Methods The TOPICAL study was a 4-period, partially-randomised, controlled, crossover study to investigate four aerosolised approaches in IPF subjects. Nine subjects were randomised to receive 99m Technetium-labelled monodisperse salbutamol (1.5 μm or 6 μm; periods 1 and 2). Subjects also received radio-labelled salbutamol using a polydisperse nebuliser (period 3) and unlabelled salbutamol (400 μg) using a polydisperse pressurized metered dose inhaler with volumatic spacer (pMDI; period 4). Results Small monodisperse particles (1.5 μm) achieved significantly better total lung deposition (TLD, mean % ± SD) than larger particles (6 μm), where polydisperse nebulisation was poor; (TLD, 64.93 ± 10.72; 50.46 ± 17.04; 8.19 ± 7.72, respectively). Small monodisperse particles (1.5 μm) achieved significantly better lung penetration (mean % ± SD) than larger particles (6 μm), and polydisperse nebulisation showed lung penetration similar to the small particles; PI (mean ± SD) 0.8 ± 0.16, 0.49 ± 0.21, and 0.73 ± 0.19, respectively. Higher dose-normalised plasma salbutamol levels were observed following monodisperse 1.5 μm and 6 μm particles, compared to polydisperse pMDI inhalation, while lowest plasma levels were observed following polydisperse nebulisation. Conclusion Our data is the first systematic investigation of inhaled drug delivery in fibrotic lung disease. We provide evidence that inhaled drugs can be optimised to reach the peripheral areas of the lung where active scarring occurs in IPF. Trial registration This trial was registered on clinicaltrials.gov ( NCT01457261 ).

Abstract Background: Two-dimensional gamma scintigraphy is an important technique used to evaluate the lung deposition from inhaled therapeutic aerosols. Images are divided into regions of interest and deposition indices are derived to quantify aerosol distribution within the intrapulmonary airways. In this article, we compared the different approaches that have been historically used between different laboratories for geometrically defining lung regions of interest. We evaluated the effect of these different approaches on the derived indices classically used to assess inhaled aerosol deposition in the lungs. Our primary intention was to assess the ability of different regional lung templates to discriminate between central and peripheral airway deposition patterns generated by inhaling aerosols of different particle sizes. Methods: We investigated six methods most commonly reported in the scientific literature to define lung regions of interest and assessed how different each of the derived regional lung indices were between the methods to quantify regional lung deposition. We used monodisperse albuterol aerosols of differing particle size (1.5, 3, and 6 μm) in five mild asthmatic subjects [forced expiratory volume in 1 sec (FEV1) 90% predicted] to test the different approaches of each laboratory. Results: We observed the areas of geometry used to delineate central (C) and peripheral (P) lung regions of interest varied markedly between different laboratories. There was greater similarity between methods in values of penetration index (PI), defined as P/C aerosol counts normalized by P/C krypton ventilation counts, compared to nonnormalized C/P or P/C aerosol count-ratios. Normalizing the aerosol deposition P/C count-ratios by the ventilation P/C count-ratios, reduced the variability of the data. There was dependence of the regional lung deposition indices on the size of the P region of interest in that, as P increased, C/P count-ratios decreased and P/C count-ratios increased, whereas PI was less affected by variations in the P area. We found particle size, itself, strongly influenced the indices of regional aerosol deposition such that C/P count-ratios increased with increasing particle size for each method and conversely, P/C count-ratios and PI decreased. Conclusions: Different approaches used to determine pulmonary regions of interest and quantify aerosol deposition produce different results. Our research highlights a genuine need for a consensus to standardize the methodology to facilitate data comparison between laboratories on aerosol deposition.

Airway neutrophil levels are increased in patients with severe asthma and during asthma exacerbations. Long-acting β2-agonists (LABAs), such as formoterol, reduce the number of asthma exacerbations. While β2-agonists may affect neutrophil function in vitro, it is uncertain whether they have effects on neutrophilic inflammation in asthmatic patients in vivo. In a double-blind randomized crossover study, we evaluated the effects of 4 weeks of treatment with formoterol (Turbuhaler), 24 μg bid, compared to placebo on sputum neutrophil numbers and interleukin (IL)-8 levels in asthmatic patients. Therapy with budesonide (administered via Turbuhaler), 400 μg bid for 4 weeks, was added at the end as a “gold standard” antiinflammatory effect comparison. We studied 15 steroid-naïve nonsmoking patients who ranged from 19 to 51 years of age and had mild persistent asthma. Formoterol therapy significantly reduced sputum IL-8 levels and neutrophil numbers compared to placebo. There was a significant correlation between the reduction in sputum IL-8 levels and the number of neutrophils, indicating that formoterol may attenuate neutrophilic airway inflammation by inhibiting IL-8 production. Our data suggest that the LABA formoterol reduces neutrophilic airway inflammation in patients with mild asthma and that this might be beneficial in preventing asthma exacerbations.

IntroductionAsthma is a variable lung condition whereby patients experience periods of controlled and uncontrolled asthma symptoms. Patients who experience prolonged periods of uncontrolled asthma have a higher incidence of exacerbations and increased morbidity and mortality rates. The ability to determine and to predict levels of asthma control and the occurrence of exacerbations is crucial in asthma management. Therefore, we aimed to determine to what extent physiological, behavioural and environmental data, obtained by mobile healthcare (mHealth) and home-monitoring sensors, as well as patient characteristics, can be used to predict episodes of uncontrolled asthma and the onset of asthma exacerbations.Methods and analysisIn an 1-year observational study, patients will be provided with mHealth and home-monitoring systems to record daily measurements for the first-month (phase I) and weekly measurements during a follow-up period of 11 months (phase II). Our study population consists of 150 patients, aged ≥18 years, with a clinician's diagnosis of asthma, currently on controller medication, with uncontrolled asthma and/or minimally one exacerbation in the past 12 months. They will be enrolled over three participating centres, including Leiden, London and Manchester. Our main outcomes are the association between physiological, behavioural and environmental data and (1) the loss of asthma control and (2) the occurrence of asthma exacerbations.EthicsThis study was approved by the Medical Ethics Committee of the Leiden University Medical Center in the Netherlands and by the NHS ethics service in the UK.Trial registration numberNCT02774772.

Abstract Rationale Bronchial thermoplasty (BT) is designed to reduce airway smooth muscle and improve asthma control. Objectives This study was conducted to determine the safety and efficacy of this procedure in subjects with symptomatic, severe asthma. Methods Adults who were symptomatic despite treatment with fluticasone or equivalent at more than 750 μg/day, a long-acting β2-agonist, and other medications, which could include 30 mg or less of oral prednisolone/day, were randomized to BT or to a control group. After treatment, subjects entered a 16-week steroid stable phase (Weeks 6–22), a 14-week steroid wean phase (Weeks 22–36), and a 16-week reduced steroid phase (Weeks 36–52). Measurements and Main Results BT resulted in a transient worsening of asthma symptoms. Seven hospitalizations for respiratory symptoms occurred in 4 of 15 BT subjects during the treatment period. Five hospitalizations were within 3 days of treatment. Two subjects had segmental collapse involving the most recently treated lobe; one required bronchoscopy and aspiration of a mucus plug. There were no hospitalizations during this period in the 17 control subjects. The rate of hospitalizations was similar in both groups in the post-treatment period. At 22 weeks, BT subjects had significant improvements versus control subjects in rescue medication use (−26.6 ± 40.1 vs. −1.5 ± 11.7 puffs/7 d, P < 0.05), prebronchodilator FEV1% predicted (14.9 ± 17.4 vs. −0.94 ± 22.3%, P = 0.04), and Asthma Control Questionnaire scores (−1.04 ± 1.03 vs. −0.13 ± 1.00, P = 0.02). Improvements in rescue medication use and Asthma Control Questionnaire scores remained significantly different from those of controls at 52 weeks. Conclusions BT is associated with a short-term increase in asthma-related morbidity. However, there is preliminary evidence of long-lasting improvement in asthma control. Clinical trial registered with www.clinicaltrials.gov (NCT00214539).

Abstract Rationale Despite long-term therapy with corticosteroids, patients with severe asthma develop irreversible airway obstruction. Objectives To evaluate if there are structural and functional differences in the airway epithelium in severe asthma associated with airway remodeling. Methods In bronchial biopsies from 21 normal subjects, 11 subjects with chronic bronchitis, 9 subjects with mild asthma, and 31 subjects with severe asthma, we evaluated epithelial cell morphology: epithelial thickness, lamina reticularis (LR) thickness, and epithelial desquamation. Levels of retinoblastoma protein (Rb), Ki67, and Bcl-2 were measured, reflecting cellular proliferation and death. Terminal deoxynucleotidyl-mediated dUTP nick end labeling (TUNEL) was used to study cellular apoptosis. Measurements and Main Results Airway epithelial and LR thickness was greater in subjects with severe asthma compared with those with mild asthma, normal subjects, and diseased control subjects (p = 0.009 and 0.033, respectively). There was no significant difference in epithelial desquamation between groups. Active, hypophosphorylated Rb expression was decreased (p = 0.002) and Ki67 was increased (p < 0.01) in the epithelium of subjects with severe asthma as compared with normal subjects, indicating increased cellular proliferation. Bcl-2 expression was decreased (p < 0.001), indicating decreased cell death suppression. There was a greater level of apoptotic activity in the airway biopsy in subjects with severe asthma as compared with the normal subjects using the TUNEL assay (p = 0.002), suggesting increased cell death. Conclusions In subjects with severe asthma, as compared with subjects with mild asthma, normal subjects, and diseased control subjects, we found novel evidence of increased cellular proliferation in the airway contributing to a thickened epithelium and LR. These changes may contribute to the progressive decline in lung function and airway remodeling in patients with severe asthma.

Background Multilevel data integration is becoming a major area of research in systems biology. Within this area, multi-‘omics datasets on complex diseases are becoming more readily available and there is a need to set standards and good practices for integrated analysis of biological, clinical and environmental data. We present a framework to plan and generate single and multi-‘omics signatures of disease states. Methods The framework is divided into four major steps: dataset subsetting, feature filtering, ‘omics-based clustering and biomarker identification. Results We illustrate the usefulness of this framework by identifying potential patient clusters based on integrated multi-‘omics signatures in a publicly available ovarian cystadenocarcinoma dataset. The analysis generated a higher number of stable and clinically relevant clusters than previously reported, and enabled the generation of predictive models of patient outcomes. Conclusions This framework will help health researchers plan and perform multi-‘omics big data analyses to generate hypotheses and make sense of their rich, diverse and ever growing datasets, to enable implementation of translational P4 medicine.