Vulnerability to acid reflux of the airway epithelium in severe asthma

Abstract

BackgroundSevere asthma is associated with multiple co-morbidities, including gastro-oesophageal reflux disease (GORD) which can contribute to exacerbation frequency and poor quality of life. Since epithelial dysfunction is an important feature in asthma, we hypothesised that in severe asthma the bronchial epithelium is more susceptible to the effects of acid reflux.MethodsWe developed an in vitro model of GORD using differentiated bronchial epithelial cells (BECs) from normal or severe asthmatic donors exposed to a combination of pepsin, acid pH, and bile acids using a multiple challenge protocol (MCP-PAB). We also analysed bronchial biopsies and undertook RNA-sequencing of bronchial brushings from controls and severe asthmatics without or with GORD.ResultsExposure of BECs to the MCP-PAB caused structural disruption, increased permeability, IL-33 expression, inflammatory mediator release and changes in gene expression for multiple biological processes. Cultures from severe asthmatics were significantly more affected than those from healthy donors. Analysis of bronchial biopsies confirmed increased IL-33 expression in severe asthmatics with GORD. RNA-sequencing of bronchial brushings from this group identified 15 of the top 37 dysregulated genes found in MCP-PAB treated BECs, including genes involved in oxidative stress responses.ConclusionsBy affecting epithelial permeability, GORD may increase exposure of the airway submucosa to allergens and pathogens, resulting in increased risk of inflammation and exacerbations. Clinical implication: These results suggest the need for research into alternative therapeutic management of GORD in severe asthma.

Elevated Saliva Pepsin Concentration as a Risk Factor for Asthma in Children with Allergic Rhinitis: A Preliminary Study

“…15 This was consistent with the results of an in vitro experiment, which indicated that refluxate exposure could lead to bronchial epithelial damage, barrier leakiness, and/or neutrophil breach of the epithelium, highlighting the crucial role of pepsin in exacerbating asthma. 5 The aforementioned results also indicated the significance of proximal reflux, also known as laryngopharyngeal reflux (LPR), in exacerbating asthma. LPR is characterized by the reflux of gastric acid and refluxate (containing pepsin) above the upper esophageal sphincter.…”

“…In vitro experiments suggested that pepsin exposure disrupts respiratory epithelium and causes direct contact between submucosal tissue and allergens and pathogens. 5 Thus, pepsin concentration in upper respiratory secretions could be theoretically an indicator of asthma risk. To our knowledge, no study has yet assessed the role of pepsin concentration in pediatric asthma risk.…”

Phenomic Network Analysis for Depression Reveals Comorbidity Architecture, Genomic Relationships, and Pleiotropic Variants

“…Phenotypic comorbidity between asthma and GORD has been widely reported (12; 7), whereas, to the best of our knowledge, evidence for a causal link between these two disorders has not been suggested until now. We used SNP effects as instruments and we provided insights into possible relationships between asthma and GORD; biological explanations explaining such causal relationships might be due to the epithelial dysfunction in asthma, since such patients are more vulnerable to acid reflux (81). Our results also point towards a uni-directional causality from BMI to depression.…”

Non-Invasive, MultiOmic and MultiCompartmental Biomarkers of Reflux Disease: A Systematic Review

“…(8–10) Extraesophageal manifestations, include laryngopharyngeal disease (LPR), may lead to complications such as erosive esophagitis (EE) and Barrett’s Esophagus (BE). (11–15) An estimated 15% of all visits to otolaryngologists are due to LPR. (16)…”

“…(8)(9)(10) Extraesophageal manifestations, include laryngopharyngeal disease (LPR), may lead to complications such as erosive esophagitis (EE) and Barrett's Esophagus (BE). (11)(12)(13)(14)(15) An estimated 15% of all visits to otolaryngologists are due to LPR. (16) GERD can be diagnosed clinically as per the Montreal consensus or it can be defined using invasive testing as per the Porto and Lyon consensus statements.…”