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Vulnerability to acid reflux of the airway epithelium in severe asthma

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.

0903-1936
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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Perotin, Jeanne-Marie
48f760d9-7f2c-4e46-b6f7-cd3b9094bc19
Wheway, Gabrielle
2e547e5d-b921-4243-a071-2208fd4cc090
Tariq, Kamran
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Azim, Adnan
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Ridley, Robert A
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Ward, Jonathan A
a8107b98-069d-4263-bd70-d29d79f07edc
Schofield, James Pr
b6d3a808-50ac-4365-bc0d-80da333a4ae7
Barber, Clair
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Howarth, Peter
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Davies, Donna E
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Djukanovic, Ratko
d9a45ee7-6a80-4d84-a0ed-10962660a98d

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).

Record type: Article

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.

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13993003.01634-2021.full - Accepted Manuscript
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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.

Identifiers

Local EPrints ID: 454502
URI: http://eprints.soton.ac.uk/id/eprint/454502
ISSN: 0903-1936
PURE UUID: e6476a4b-a8f6-470e-b738-df77bd6e0fcb
ORCID for Gabrielle Wheway: ORCID iD orcid.org/0000-0002-0494-0783
ORCID for Jonathan A Ward: ORCID iD orcid.org/0000-0002-9278-0002
ORCID for Clair Barber: ORCID iD orcid.org/0000-0001-5335-5129
ORCID for Donna E Davies: ORCID iD orcid.org/0000-0002-5117-2991
ORCID for Ratko Djukanovic: ORCID iD orcid.org/0000-0001-6039-5612

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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 ORCID iD
Author: James Pr Schofield
Author: Clair Barber ORCID iD
Author: Peter Howarth
Author: Donna E Davies ORCID iD

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