Airway epithelial transcriptional response to daily high-dose inhaled corticosteroids in asthma.

Rationale: Inhaled corticosteroids are the cornerstone of asthma treatment, yet the epithelial pathways mediating their anti-inflammatory effects and their relationship to clinical traits remain incompletely understood. The objective of the present study was to investigate airway epithelial transcriptomic changes in steroid-free patients with asthma following treatment with high-dose inhaled corticosteroids. Methods: Bronchial brushings from 20 steroid-free patients with asthma were obtained during bronchoscopy before and after 6 weeks of high-dose budesonide treatment, and mRNA-sequencing was performed. Airway epithelial gene expression was analysed by weighted gene co-expression network analysis (WGCNA) to identify gene networks and profiles associated with inhaled corticosteroid treatment response. Results: Four steroid-response clusters were identified; one metabolic cluster related to oxidative phosphorylation, which was upregulated, and three immunological clusters associated with T-cell activation and immune cell and mast cell responses, where gene expression was downregulated following inhaled corticosteroid treatment. Conclusions: In steroid-free patients with asthma, inhaled corticosteroids modulate airway epithelial gene networks by enhancing oxidative phosphorylation and suppressing immune and mast cell pathways. Baseline clinical traits predicted the strength of these responses, suggesting potential biomarkers for stratifying treatment with inhaled corticosteroids in asthma.