Severe 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.
We developed an 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.
Exposure 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.
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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About The Expert
Jeanne-Marie Perotin
- NIHR Southampton Biomedical Research Centre, University Hospital Southampton, UK jmperotin-collard@chu-reims.fr.
- Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.
- Department of Respiratory Diseases, UMRS1250, University Hospital of Reims, France.
Gabrielle Wheway
- Human Development and Health, University of Southampton Faculty of Medicine, Southampton, UK.
- Institute for Life Sciences, University of Southampton, Southampton, UK.
Kamran Tariq
- NIHR Southampton Biomedical Research Centre, University Hospital Southampton, UK.
- Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.
Adnan Azim
- NIHR Southampton Biomedical Research Centre, University Hospital Southampton, UK.
- Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.
Robert A Ridley
- Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.
Jonathan A Ward
- The Histochemistry Research Unit, Faculty of Medicine, University of Southampton, Southampton, UK.
James Pr Schofield
- Centre for Proteomic Research, Institute for Life Sciences, University of Southampton, Southampton, UK.
Clair Barber
- NIHR Southampton Biomedical Research Centre, University Hospital Southampton, UK.
- Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.
Peter Howarth
- NIHR Southampton Biomedical Research Centre, University Hospital Southampton, UK.
- Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.
Donna E Davies
- NIHR Southampton Biomedical Research Centre, University Hospital Southampton, UK.
- Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.
- Institute for Life Sciences, University of Southampton, Southampton, UK.
- joint senior authors.
Ratko Djukanovic
- NIHR Southampton Biomedical Research Centre, University Hospital Southampton, UK.
- Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.
- Institute for Life Sciences, University of Southampton, Southampton, UK.
- joint senior authors.
References
PubMed