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.

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.

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.

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.

严重哮喘与多种合并症有关，包括胃食管反流病 (GORD)，这可能导致哮喘发作频率和生活质量差。由于上皮功能障碍是哮喘的一个重要特征，我们假设在严重哮喘中支气管上皮更容易受到酸反流的影响。

我们使用多重攻击方案 (MCP-PAB) 使用来自暴露于胃蛋白酶、酸性 pH 值和胆汁酸组合的正常或严重哮喘供体的分化支气管上皮细胞 (BEC) 开发了体外GORD 模型。此外，我们分析了支气管活检，并对对照组和严重哮喘患者（未使用或使用 GORD）的支气管刷毛进行了 RNA 测序。

BEC 暴露于 MCP-PAB 会导致结构破坏、通透性增加、白细胞介素 (IL)-33 表达、炎症介质释放和多种生物过程的基因表达变化。来自严重哮喘患者的培养物比来自健康供体的培养物受到的影响明显更大。支气管活检分析证实，在患有 GORD 的重度哮喘患者中 IL-33 表达增加。对该组支气管刷的 RNA 测序确定了在 MCP-PAB 处理的 BEC 中发现的前 37 个失调基因中的 15 个，包括参与氧化应激反应的基因。

通过影响上皮通透性，GORD 可能会增加气道黏膜下层对过敏原和病原体的暴露，从而增加炎症和恶化的风险。这些结果表明需要对严重哮喘中 GORD 的替代治疗管理进行研究。