The effects of inhaled corticosteroids on healthy airways

<bold>Introduction:</bold> The effects of inhaled corticosteroids (ICS) on healthy airways are poorly described. Delineating their effects on gene expression in health, without the confounding changes generated by changes in disease-related genes, will enable more precise analysis of data in severe asthma. <bold>Methods:</bold> Randomised, open-label, single-blinded bronchoscopy study of high dose ICS therapy in 30 healthy adults randomised 2:1 to 4 weeks fluticasone propionate Accuhaler 500 mcg bd or no treatment. Biopsies and brushings analysed by immunohistochemistry, bulk RNA sequencing, DNA methylation array and metagenomics. <bold>Results:</bold> Blood eosinophils increased after 4 weeks in controls v ICS. This was not related to atopic status. Blood neutrophils, FeNO or FEV1 did not differ between groups. There was a significant between-group difference in change in lamina propria eosinophils. The genes most upregulated by ICS related to steroid metabolism, cellular proliferation, cellular metabolism and cytoskeletal changes. By contrast the most downregulated genes in both brushings and biopsies were key mediators of type 2 inflammation (FCER1A, CPA3, IL33, CLEC10A, SERPINB10 and CCR5) or T cell mediated adaptive immunity (TARP, TRBC1, TRBC2, PTPN22, TRAC, CD2, CD8A, HLA-DQB2, CD96, PTPN7). We observed minimal differences in the microbiome or DNA methylation. <bold>Conclusions:</bold> We defined genes altered directly by corticosteroid therapy without confounding by disease. Strikingly, even in health, the most downregulated genes were canonical markers of type 2 inflammation. This implies that homeostasis in health involves tonic type 2 signalling in the airway mucosa, which is very sensitive to corticosteroids.