Vulnerability to acid reflux of the airway epithelium in severe asthma
Vulnerability to acid reflux of the airway epithelium in severe asthma
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.
Perotin, Jeanne-Marie
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Wheway, Gabrielle
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Tariq, Kamran
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Azim, Adnan
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Ridley, Robert A
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Ward, Jonathan A
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Schofield, James Pr
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Barber, Clair
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Howarth, Peter
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Davies, Donna E
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Djukanovic, Ratko
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1 August 2022
Perotin, Jeanne-Marie
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Wheway, Gabrielle
2e547e5d-b921-4243-a071-2208fd4cc090
Tariq, Kamran
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Azim, Adnan
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Ridley, Robert A
863f7655-4c32-47f8-8f04-76807a5bb63b
Ward, Jonathan A
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Schofield, James Pr
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Barber, Clair
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Howarth, Peter
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Davies, Donna E
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Djukanovic, Ratko
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Perotin, Jeanne-Marie, Wheway, Gabrielle, Tariq, Kamran, Azim, Adnan, Ridley, Robert A, Ward, Jonathan A, Schofield, James Pr, Barber, Clair, Howarth, Peter, Davies, Donna E and Djukanovic, Ratko
(2022)
Vulnerability to acid reflux of the airway epithelium in severe asthma.
The European respiratory journal, 60 (2), [2101634].
(doi:10.1183/13993003.01634-2021).
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.
Text
13993003.01634-2021.full
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More information
Accepted/In Press date: 10 December 2021
e-pub ahead of print date: 7 January 2022
Published date: 1 August 2022
Additional Information:
Funding Information:
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.
Publisher Copyright:
Copyright © The authors 2022.
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Local EPrints ID: 454502
URI: http://eprints.soton.ac.uk/id/eprint/454502
ISSN: 0903-1936
PURE UUID: e6476a4b-a8f6-470e-b738-df77bd6e0fcb
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Date deposited: 14 Feb 2022 17:40
Last modified: 17 Mar 2024 07:05
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Contributors
Author:
Jeanne-Marie Perotin
Author:
Kamran Tariq
Author:
Adnan Azim
Author:
Robert A Ridley
Author:
Jonathan A Ward
Author:
James Pr Schofield
Author:
Clair Barber
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