Project description:Severe asthma induces substantial mortality and chronic disability due to intractable airway obstruction, which may become resistant to currently available therapies including corticosteroids and b-adrenergic agonist bronchodilators. A key effector of these changes is exaggerated airway smooth muscle (ASM) cell contraction to spasmogens. Unfortunately, no drugs in clinical use effectively prevent ASM hyperresponsiveness in asthma across all severities. Here we show that N-cadherin, a plasma membrane associated cell-cell adhesion protein upregulated in ASM cells derived from patients with severe asthma, is required for the development of airway obstruction induced by allergic airway inflammation in mice. Pharmacological inhibition of N-cadherin by ADH-1 reduced airway hyperresponsiveness independent of allergic inflammation. ADH-1 prevented bronchoconstriction and actively promoted bronchodilation of airways ex vivo. In human ASM cells, ADH-1 inhibited agonist-induced contraction by disrupting N-cadherin-d-catenin interactions, which decreased intracellular actin remodeling. These data provide evidence for an intercellular communication pathway mediating ASM contraction and identify N-cadherin as a potential therapeutic target for inhibiting bronchoconstriction in asthma.
Project description:Background: Asthma is highly heterogeneous and severity evaluation is key to asthma management. DNA methylation (DNAm) contributes to asthma pathogenesis. This study aimed to identify nasal epithelial DNAm differences between severe and non-severe asthmatic children and evaluate the impact of environmental exposures. Methods: Thirty-three non-severe and 22 severe asthmatic African-American children were included in an epigenome-wide association study. Genome-wide nasal epithelial DNAm and gene expression were measured. CpG sites associated with asthma severity and environmental exposures and predictive of severe asthma were identified. DNAm was correlated with gene expression. Enrichment for transcription factor (TF) binding sites or histone modifications surrounding DNAm differences were determined. Results: We identified 816 differentially methylated CpG positions (DMPs) and 10 differentially methylated regions (DMRs) associated with asthma severity. Three DMPs exhibited discriminatory ability for severe asthma. Intriguingly, six DMPs were simultaneously associated with asthma, allergic asthma, total IgE, environmental IgE, and FeNO in an independent cohort of children. 27 DMPs were associated with traffic-related air pollution or secondhand smoke. DNAm at 22 DMPs were altered by diesel particles or allergen in human bronchial epithelial cells. DNAm levels at 39 DMPs were correlated with mRNA expression. Proximal to 816 DMPs, three histone marks and several TFs involved in asthma pathogenesis were enriched. Conclusions: Significant differences in nasal epithelial DNAm were observed between non-severe and severe asthma in African-American children, a subset of which may be useful to predict disease severity. These CpG sites are subject to the influences of environmental exposures and may regulate gene expression.
Project description:Management of severe asthma remains a challenge despite treatment with glucocorticosteroid therapy. The majority of studies investigating disease mechanisms in treatment-resistant severe asthma have previously focused on the large central airways, with very few utilizing transcriptomic approaches. The small peripheral airways, which comprise the majority of the airway surface area, remain an unexplored area in severe asthma and were targeted for global epithelial gene expression profiling in this study.
Project description:Gene expression profiles were generated from induced sputum samples in asthma and healthy controls. The study identified differential gene expression and pathways in severe asthma.
Project description:Therapies targeting interleukin-5 (IL-5) or its receptor (IL-5Rα) are used to treat patients with severe eosinophilic asthma. The therapeutic effect are considered being the suppression of eosinophil activation and elimination. However, the impact of these therapies on mast cells (MCs) and their progenitors has remained largely unexplored. We investigate whether targeting the IL-5 pathway in severe asthma patients could reduce blood MC progenitors
Project description:Severe asthma is a complex disease with different inflammatory phenotypes. Transcriptomic profiling has contributed to understanding the pathogenesis of asthma, especially type-2 inflammation; however, there is still poor understanding of non-eosinophilic asthma, and consequently there are limited treatment options. The aim of this study was to determine transcriptomic profiles in endobronchial biopsies of adults with severe asthma and different inflammatory phenotypes (neutrophilic, eosinophilic and paucigranulocytic) compared with healthy controls.
Project description:Severe asthma is a clinically and physiologically heterogeneous disease. Benralizumab is a monoclonal antibody which binds the alpha chain of the interleukin-5 receptor and used for severe eosinophilic asthma worldwide. However, not all eosinophilic asthma patients will benefit from benralizumab due to heterogeneity of this disease. Therefore, we performed comprehensive gene expression analysis of whole blood cells that examine severe asthma disease heterogeneity in response to benralizumab. This study is the first to perform comprehensive transcriptome analysis of whole blood cells to identify transcriptomic endotypes of severe asthma clusters that correlate with benralizumab response. The identified transcriptomic endotypes of severe asthma clusters are associated with gene signatures of eosinophils and neutrophilis.
Project description:In this study we explore the underlying differences in bronchial epithelial cells from asthma patinets compared to healthy controls. In addition we also explore the differential gene expression of severe asthma patients compared to mild and moderate asthma patients to determine if there are genes that lead to severity of the disease