Abstract
Background Severe asthma is associated with multiple comorbidities, 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.
Methods We 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). In addition, we analysed bronchial biopsies and undertook RNA sequencing of bronchial brushings from controls and severe asthmatics without or with GORD.
Results Exposure of BECs to the MCP-PAB caused structural disruption, increased permeability, interleukin (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.
Conclusions and clinical implication By affecting epithelial permeability, GORD may increase exposure of the airway submucosa to allergens and pathogens, resulting in increased risk of inflammation and exacerbations. These results suggest the need for research into alternative therapeutic management of GORD in severe asthma.
Abstract
Using a combination of in vitro and ex vivo approaches, this study identified reflux causing significant effects on the bronchial epithelial structure and function, which were greater in patients with severe asthma https://bit.ly/31XV9tq
Footnotes
Author contributions: Substantial contributions to the conception or design of the work: J-M. Perotin, G. Wheway, J.P.R. Schofield, P. Howarth, D.E. Davies and R. Djukanovic. Acquisition, analysis or interpretation of the data: J-M. Perotin, G. Wheway, K. Tariq, A. Azim, R.A. Ridley, J.A. Ward, C. Barber, D.E. Davies and R. Djukanovic. Drafting the manuscript or revising it critically for important intellectual content: J-M. Perotin, D.E. Davies and R. Djukanovic. Final approval of the manuscript version to be published: all authors
Conflict of interest: J-M. Perotin, G. Wheway, K. Tariq, A. Azim, R.A. Ridley, J.A. Ward, C. Barber and D.E. Davies have nothing to disclose. J.P.R. Schofield reports being director and shareholder in TopMD Precision Medicine Ltd. P. Howarth reports personal fees from GSK outside the submitted work. R. Djukanovic reports receiving fees for lectures at symposia organised by Novartis, AstraZeneca and TEVA, consultation for TEVA and Novartis as member of advisory boards, and participation in a scientific discussion about asthma organised by GlaxoSmithKline; and is a co-founder and current consultant, and has shares in Synairgen, a University of Southampton spin-out company.
Support statement: J-M. Perotin acknowledges the support of the European Respiratory Society (fellowship LTRF 2017) and of the Asthma, Allergy and Inflammation Research Charity. Funding information for this article has been deposited with the Crossref Funder Registry.
- Received June 9, 2021.
- Accepted December 10, 2021.
- Copyright ©The authors 2022. For reproduction rights and permissions contact permissions{at}ersnet.org
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