Identification of bronchial epithelial genes associated with type 2 eosinophilic inflammation in asthma.

BACKGROUND

Airway inflammation plays a critical role in asthma pathogenesis and pathophysiology, but the molecular pathways contributing to airway inflammation are not fully known, particularly type 2 (T2) inflammation characterized by both eosinophilia and higher fractional exhaled nitric oxide (Feno) levels.

OBJECTIVE

We sought to identify genes whose level of expression in epithelial brushing samples were associated with both bronchoalveolar lavage (BAL) eosinophilia and generation of Feno.

METHODS

We performed segmental allergen bronchoprovocation (SBP-Ag) in participants with asthma, then RNA sequencing analyses of BAL cells and brushing samples before and 48 hours after SBP-Ag to identify regulation of eosinophil recruitment and Feno changes.

RESULTS

Allergen bronchoprovocation increased Feno levels, which correlated with eosinophilia. Thirteen genes were identified in brushing samples, whose expression changed in response to SBP-Ag and correlated with both airway eosinophilia and Feno levels after SBP-Ag. Among these 13 genes, epithelial cell product CDH26/cadherin-26 contributed to the amplification of T2 inflammation, as reflected by eosinophilia and Feno, and causal mediation analyses with pro-T2 and proeosinophilic cytokine mediators in BAL fluids. Among the genes associated with reduced eosinophilia and Feno, HEY2 is known to enhance cell proliferation, migration, invasion, and epithelial-to-mesenchymal transition, as well as to reduce apoptosis.

CONCLUSION

This unbiased RNA sequencing analysis in participants with allergic asthma revealed several epithelial cell genes, particularly CDH26, that may be critical for the development or augmentation of T2 inflammation in asthma.