Novel therapies for gastroesophageal reflux disease (GERD) are needed in patients with severe asthma, given that GERD is a known contributor to exacerbation frequency and poor quality of life. The current analysis used a combination of in vitro and ex vivo approaches to elucidate further the underlying mechanisms of GERD-associated dysregulation of the airway epithelium in patients with severe asthma, according to findings published in the European Respiratory Journal.
Because epithelial dysfunction is a key feature in patients with asthma, investigators hypothesized that the bronchial epithelium would be more susceptible to the effects of acid reflux in these patients. To investigate this, the researchers developed an in vitro model of GERD by utilizing fully differentiated air-liquid interface (ALI) cultures of primary bronchial epithelial cells (BECs) from healthy donors and from donors with severe asthma who were exposed to a combination of pepsin, acid pH, and bile acids via use of a multiple challenge protocol (MCP-PAB). Bronchial biopsies and RNA-sequencing of bronchial brushings from both those in the control group and those with severe asthma, with and without GERD, were also analyzed.
Individuals with severe asthma and participants for the control group were recruited prospectively and evaluated for GERD with the use of 24-hour pH/impedance studies. Patients with severe asthma were further stratified into 1 of the following 3 groups: (1) those with documented GERD who were receiving no proton pump inhibitor (PPI) treatment; (2) those with documented GERD who were receiving PPI therapy; and (3) those without GERD.
In order to examine the effect of GERD on the airway epithelium of patients with severe asthma, ALI cultures were obtained from bronchial brushings of participants with severe asthma and GERD who were receiving a PPI (n=8) and from individuals in the control group (n=5). These cultures were exposed for 30 minutes to MCP-PAB conditions that consisted of pepsin 50 µg/mL and chenodeoxycholic acid 250 µM at pH 5.
Results of the study showed that exposure of BECs to the MCP-PAB was associated with structural disruption, increased permeability, interleukin (IL)-33 expression, inflammatory mediator release, and changes in gene expression for many biological processes. Cultures obtained from patients with severe asthma were affected more significantly than cultures from healthy individuals in the control group. When bronchial biopsies were analyzed, increased IL-33 expression in patients with severe asthma and GERD was confirmed. RNA-sequencing performed in bronchial biopsies from this group of participants identified 15 of the top 37 dysregulated genes detected in MCP-PAB–treated BECs, including genes that are involved in oxidative stress responses.
The investigators concluded that the findings from the current analysis identified reflux as the cause of significant effects on bronchial epithelial structure and function, which were greater in individuals with severe asthma than in healthy individuals. Research into alternative methods for the management of GERD in patients with severe asthma is thus warranted.
Disclosure: Some of the study authors have declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.
Perotin JM, Wheway G, Tariq K, et al. Vulnerability to acid reflux of the airway epithelium in severe asthma. Eur Respir J. Published online January 7, 2022. doi:10.1183/13993003.01634-2021
This article originally appeared on Pulmonology Advisor