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BACKGROUNDMucus plugs form in acute asthma and persist in chronic disease. Although eosinophils are implicated in mechanisms of mucus pathology, many mechanistic details about mucus plug formation and persistence in asthma are unknown.METHODSUsing histology and spatial, single-cell proteomics, we characterized mucus-plugged airways from nontransplantable donor lungs of 14 patients with asthma (9 with fatal asthma and 5 with nonfatal asthma) and individuals acting as controls (10 with chronic obstructive pulmonary disease and 14 free of lung disease). Additionally, we used an airway epithelial cell-eosinophil (AEC-eosinophil) coculture model to explore how AEC mucus affects eosinophil degranulation.RESULTSAsthma mucus plugs were tethered to airways showing infiltration with innate lymphoid type 2 cells and hyperplasia of smooth muscle cells and MUC5AC-expressing goblet cells. Asthma mucus plugs were infiltrated with immune cells that were mostly dual positive for eosinophil peroxidase (EPX) and neutrophil elastase, suggesting that neutrophils internalize EPX from degranulating eosinophils. Indeed, eosinophils exposed to mucus from IL-13-activated AECs underwent CD11b- and glycan-dependent cytolytic degranulation. Dual-positive granulocytes varied in frequency in mucus plugs. Whereas paucigranulocytic plugs were MUC5AC rich, granulocytic plugs had a mix of MUC5AC, MUC5B, and extracellular DNA traps. Paucigranulocytic plugs occurred more frequently in (acute) fatal asthma and granulocytic plugs predominated in (chronic) nonfatal asthma.CONCLUSIONTogether, our data suggest that mucin-rich mucus plugs in fatal asthma form because of acute goblet cell degranulation in remodeled airways and that granulocytic mucus plugs in chronic asthma persist because of a sustaining niche characterized by epithelial cell-mucin-granulocyte cross-talk.FUNDINGNIH grants HL080414, HL107202, and AI077439.

Airway remodeling in asthma has been classically considered to be the result of inflammatory changes. In this study, the investigators show that bronchoconstriction alone can result in changes consistent with airway remodeling. Asthma is a common chronic respiratory condition characterized clinically by an excessive tendency toward reversible airway narrowing. This may arise in response to everyday environmental exposure and is worsened both by intercurrent infection and, in sensitized persons, by allergen exposure. In pathological terms, asthma is characterized by airway inflammation and by structural changes in airway tissues, such as epithelial goblet-cell hyperplasia, subepithelial collagen deposition, and smooth-muscle hypertrophy — collectively referred to as airway remodeling. 1 – 3 Since an inhaled-allergen challenge in atopic asthma induces eosinophilic inflammation of the airway and changes in the extracellular matrix, 4 and since a reduction in airway . . .

BackgroundTwo distinct, stable inflammatory phenotypes have been described in adults with asthma: eosinophilic and non-eosinophilic. Treatment strategies based on these phenotypes have been successful. This study evaluated sputum cytology in children with asthma to classify sputum inflammatory phenotypes and to assess their stability over time.MethodsSputum induction was performed in 51 children with severe asthma and 28 with mild to moderate asthma. Samples were classified as eosinophilic (>2.5% eosinophils), neutrophilic (>54% neutrophils); mixed granulocytic (>2.5% eosinophils, >54% neutrophils); or paucigranulocytic (≤2.5% eosinophils, ≤54% neutrophils). Sputum induction was repeated every 3 months in children with severe asthma (n=42) over a 1-year period and twice in mild to moderate asthma (n=17) over 3–6 months.Results62 children (78%) had raised levels of inflammatory cells in at least one sputum sample. In the longitudinal analysis 37 of 59 children (63%) demonstrated two or more phenotypes. Variability in sputum inflammatory phenotype was observed in both the severe and the mild to moderate asthma groups. Change in phenotype was not related to change in inhaled corticosteroid (ICS) dose or asthma control, nor was it reflected in a change in exhaled nitric oxide (FENO). 24 children (41%) fulfilled the criteria for non-eosinophilic asthma on one occasion and eosinophilic on another. There were no differences in severity, asthma control, atopy, ICS dose or forced expiratory volume in 1 s between those who were always non-eosinophilic and those always eosinophilic.ConclusionRaised levels of inflammatory cells were frequently found in children with asthma of all severities. Sputum inflammatory phenotype was not stable in children with asthma.

Airway inflammation and epithelial remodeling are two key features of asthma. IL-13 and other cytokines produced during T helper type 2 cell-driven allergic inflammation contribute to airway epithelial goblet cell metaplasia and may alter epithelial-mesenchymal signaling, leading to increased subepithelial fibrosis or hyperplasia of smooth muscle. The beneficial effects of corticosteroids in asthma could relate to their ability to directly or indirectly decrease epithelial cell activation by inflammatory cells and cytokines. To identify markers of epithelial cell dysfunction and the effects of corticosteroids on epithelial cells in asthma, we studied airway epithelial cells collected from asthmatic subjects enrolled in a randomized controlled trial of inhaled corticosteroids, from healthy subjects and from smokers (disease control). By using gene expression microarrays, we found that chloride channel, calcium-activated, family member 1 (CLCA1), periostin, and serine peptidase inhibitor, clade B (ovalbumin), member 2 (serpinB2) were up-regulated in asthma but not in smokers. Corticosteroid treatment down-regulated expression of these three genes and markedly up-regulated expression of FK506-binding protein 51 (FKBP51). Whereas high baseline expression of CLCA1, periostin, and serpinB2 was associated with a good clinical response to corticosteroids, high expression of FKBP51 was associated with a poor response. By using airway epithelial cells in culture, we found that IL-13 increased expression of CLCA1, periostin, and serpinB2, an effect that was suppressed by corticosteroids. Corticosteroids also induced expression of FKBP51. Taken together, our findings show that airway epithelial cells in asthma have a distinct activation profile and identify direct and cell-autonomous effects of corticosteroid treatment on airway epithelial cells that relate to treatment responses and can now be the focus of specific mechanistic studies.

Abstract Rationale Accumulation of eosinophils in the bronchial mucosa of individuals with asthma is considered to be a central event in the pathogenesis of asthma. In animal models, airway eosinophil recruitment and airway hyperresponsiveness in response to allergen challenge are reduced by specific targeting of interleukin-5. A previous small dose-finding study found that mepolizumab, a humanized anti–interleukin-5 monoclonal antibody, had no effect on allergen challenge in humans. Objectives To investigate the effect of three intravenous infusions of mepolizumab, 250 or 750 mg at monthly intervals, on clinical outcome measures in 362 patients with asthma experiencing persistent symptoms despite inhaled corticosteroid therapy (400–1,000 μg of beclomethasone or equivalent). Methods Multicenter, randomized, double-blind, placebo-controlled study. Measurements and Main Results Morning peak expiratory flow, forced expiratory volume in 1 second, daily β2-agonist use, symptom scores, exacerbation rates, and quality of life measures. Sputum eosinophil levels were also measured in a subgroup of 37 individuals. Mepolizumab was associated with a significant reduction in blood and sputum eosinophils in both treatment groups (blood, P < 0.001 for both doses; sputum, P = 0.006 for 250 mg and P = 0.004 for 750 mg). There were no statistically significant changes in any of the clinical end points measured. There was a nonsignificant trend for decrease in exacerbation rates in the mepolizumab 750-mg treatment group (P = 0.065). Conclusions Mepolizumab treatment does not appear to add significant clinical benefit in patients with asthma with persistent symptoms despite inhaled corticosteroid therapy. Further studies are needed to investigate the effect of mepolizumab on exacerbation rates, using protocols specifically tailored to patients with asthma with persistent airway eosinophilia.

Background:Non-eosinophilic asthma is a potentially important clinicopathological phenotype since there is evidence that it responds poorly to inhaled corticosteroid therapy. However, little is known about the underlying airway immunopathology and there are no data from placebo-controlled studies examining the effect of inhaled corticosteroids.Methods:Airway immunopathology was investigated using induced sputum, bronchial biopsies, bronchial wash and bronchoalveolar lavage in 12 patients with symptomatic eosinophilic asthma, 11 patients with non-eosinophilic asthma and 10 healthy controls. The patients with non-eosinophilic asthma and 6 different patients with eosinophilic asthma entered a randomised, double-blind, placebo-controlled crossover study in which the effects of inhaled mometasone 400 μg once daily for 8 weeks on airway responsiveness and asthma quality of life were investigated.Results:Patients with non-eosinophilic asthma had absence of eosinophils in the mucosa (median 4.4 cells/mm2 vs 23 cells/mm2 in eosinophilic asthma and 0 cells/mm2 in normal controls; p = 0.03) and normal subepithelial layer thickness (5.8 μm vs 10.3 μm in eosinophilic asthma and 5.1 μm in controls, p = 0.002). Non-eosinophilic and eosinophilic asthma groups had increased mast cell numbers in the airway smooth muscle compared with normal controls (9 vs 8 vs 0 cells/mm2, p = 0.016). Compared with placebo, 8 weeks of treatment with inhaled mometasone led to less improvement in methacholine PC20 (0.5 vs 5.5 doubling concentrations, 95% CI of difference 1.1 to 9.1; p = 0.018) and asthma quality of life (0.2 vs 1.0 points, 95% CI of difference 0.27 to 1.43; p = 0.008).Conclusions:Non-eosinophilic asthma represents a pathologically distinct disease phenotype which is characterised by the absence of airway eosinophilia, normal subepithelial layer thickness and a poor short-term response to treatment with inhaled corticosteroids.

There is increasing evidence that obesity is related to asthma development and severity. However, it is largely unknown whether weight reduction can influence asthma management, especially in children. To determine the effects of a multifactorial weight reduction intervention on asthma management in overweight/obese children with (a high risk of developing) asthma. An 18-month weight-reduction randomized controlled trial was conducted in 87 children with overweight/obesity and asthma. Every six months, measurements of anthropometry, lung function, lifestyle parameters and inflammatory markers were assessed. Analyses were performed with linear mixed models for longitudinal analyses. After 18 months, the body mass index-standard deviation score decreased by -0.14±0.29 points (p<0.01) in the intervention group and -0.12±0.34 points (p<0.01) in the control group. This change over time did not differ between groups (p>0.05). Asthma features (including asthma control and asthma-related quality of life) and lung function indices (static and dynamic) improved significantly over time in both groups. The FVC% predicted improved over time by 10.1 ± 8.7% in the intervention group (p<0.001), which was significantly greater than the 6.1 ± 8.4% in the control group (p<0.05). Clinically relevant improvements in body weight, lung function and asthma features were found in both the intervention and control group, although some effects were more pronounced in the intervention group (FVC, asthma control, and quality of life). This implies that a weight reduction intervention could be clinically beneficial for children with asthma. ClinicalTrials.gov NCT00998413.

Interleukin (IL)-5 is believed to be a key cytokine in eosinophil inflammatory infiltration in asthma. Previous clinical trials have evaluated the efficacy and safety of mepolizumab, a monoclonal antibody against IL-5, in patients with asthma. However, most of these studies were small, the conclusions were inconsistent, and the precise effects are therefore debatable. A meta-analysis of randomized placebo-controlled trials was conducted to evaluate the effect of intravenous infusion of mepolizumab on clinical outcomes in patients with asthma. Trials were searched in PubMed, Embase, Web of Science, Cochrane CENTRAL, Scopus, reviews, and reference lists of relevant articles. The outcome variables analyzed included eosinophil counts in blood and sputum, airways outcome measures, exacerbations, asthma control, and quality of life scores. Seven studies met final inclusion criteria (total n = 1131). From the pooled analyses, mepolizumab significantly reduced eosinophils in blood (MD -0.29×10(9)/L, 95% CI -0.44 to -0.14×10(9)/L, P = 0.0001) and sputum (MD -6.05%, 95% CI -9.34 to -2.77%, P = 0.0003). Mepolizumab was also associated with significantly decreased exacerbation risk than placebo (OR 0.30, 95%CI 0.13 to 0.67, P = 0.004), and with a significant improvement in the scores on the Asthma Quality of Life Questionnaire (AQLQ) (MD 0.26, 95% CI 0.03 to 0.49, P = 0.03) in patients with eosinophilic asthma. There were no statistical differences between the groups with respect to FEV1, PEF, or histamine PC20 (all P>0.05), and a non-significant trend for improvement in scores on the Juniper Asthma Control Questionnaire (JACQ) (MD -0.21, 95% CI -0.43 to 0.01, P = 0.06) in the mepolizumab group was observed. Mepolizumab reduces the risk of exacerbations and improves quality of life in patients with eosinophilic asthma, but no significant improvement in lung function outcomes was observed. Further research is required to establish the possible role of anti-IL-5 as a therapy for asthma.

Abstract Mast cell microlocalization within the airway smooth muscle bundle is an important determinant of the asthmatic phenotype. We hypothesized that mast cells migrate toward airway smooth muscle in response to smooth muscle–derived chemokines. In this study, we investigated (1) chemokine receptor expression by mast cells in the airway smooth muscle bundle in bronchial biopsies from subjects with asthma using immunohistology, (2) the concentration of chemokines in supernatants from stimulated ex vivo airway smooth muscle cells from subjects with and without asthma measured by enzyme-linked immunosorbent assay, and (3) mast cell migration toward these supernatants using chemotaxis assays. We found that CXCR3 was the most abundantly expressed chemokine receptor on human lung mast cells in the airway smooth muscle in asthma and was expressed by 100% of these mast cells compared with 47% of mast cells in the submucosa. Human lung mast cell migration was induced by airway smooth muscle cultures predominantly through activation of CXCR3. Most importantly, CXCL10 was expressed preferentially by asthmatic airway smooth muscle in bronchial biopsies and ex vivo cells compared with those from healthy control subjects. These results suggest that inhibition of the CXCL10/CXCR3 axis offers a novel target for the treatment of asthma.

BackgroundPrevious studies in adults with asthma incorporating the control of sputum eosinophils into management strategies have shown significant reductions in exacerbations. A study was undertaken to investigate whether this strategy would be successful in children with severe asthma.Methods55 children (7–17 years) with severe asthma were randomised to either a conventional symptom-based management strategy or to an inflammation-based strategy (principally sputum eosinophils). Children were seen 3-monthly over a 1-year period.ResultsThe annual rate of total and major exacerbations (courses of oral corticosteroids) was non-significantly lower in the inflammatory management group compared with the symptom management group (3.6 vs 4.8, incident rate ratio (IRR) 0.75, 95% CI 0.54 to 1.04, p=0.082; and 1.9 vs 2.7 IRR 0.73, 95% CI 0.42 to 1.28, p=0.274 for total and major exacerbations, respectively). Significantly fewer subjects in the inflammatory management group experienced an exacerbation within 28 days of a study visit. There were small non-significant differences in measures of asthma control (symptom-free days and short-acting β agonist use) favouring the inflammatory management group. There was no significant difference in the inhaled corticosteroid dose prescribed over the course of the study.ConclusionIncorporating the control of sputum eosinophils into the management algorithm did not significantly reduce overall exacerbations or improve asthma control. Exacerbations were reduced in the short term, suggesting that more frequent measurements would be needed for a clinically useful effect and that controlling inflammation may have a role to play in subgroups of children with severe asthma.