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The effects of inhaled corticosteroids on healthy airways

ABSTRACT: The effects of inhaled corticosteroids (ICS) on healthy airways are poorly defined. Our objective was to delineate the effects of ICS on gene expression in healthy airways, without confounding caused by changes in disease-related genes and disease-related alterations in ICS-responsiveness. We performed a randomised open-label bronchoscopy study of high dose ICS therapy in 30 healthy adult volunteers randomised 2:1 to i) fluticasone propionate 500 mcg bd or ii) no treatment (control), for 4 weeks. Laboratory staff were blinded to allocation. Biopsies and brushings were analysed by bulk RNA sequencing. ICS treatment upregulated 72 genes in brushings and 53 genes in biopsies, and downregulated 82 genes in brushings and 416 genes in biopsies. The most downregulated genes in both tissues were canonical markers of type-2 inflammation (FCER1A, CPA3, IL33, CLEC10A, SERPINB10 and CCR5), T cell-mediated adaptive immunity (TARP, TRBC1, TRBC2, PTPN22, TRAC, CD2, CD8A, HLA-DQB2, CD96, PTPN7), B cell immunity (CD20, immunoglobulin heavy and light chains), and innate immunity, including CD48, Hobit, RANTES, Langerin and GFI1. An IL-17-dependent gene signature was not upregulated by ICS. In healthy airways, 4-week ICS exposure reduces gene expression related to both innate and adaptive immunity, and reduces markers of type-2 inflammation. This implies that homeostasis in health involves tonic type-2 signalling in the airway mucosa, which is exquisitely sensitive to ICS.

ORGANISM(S): Homo sapiens

PROVIDER: GSE242048 | GEO | 2024/08/08

REPOSITORIES: GEO

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Project description:Introduction: In the recently completed Dutch GLUCOLD study, treatment of COPD patients with fluticasone ± salmeterol reduced the rate of decline in FEV1. These results indicate that ICS can have therapeutic efficacy in COPD. Aim: To explore the molecular mechanisms by which ICS exert their effects, we performed genome-wide gene expression profiling on bronchial biopsies from COPD patients who participated in the GLUCOLD study. Methods: An Affymetrix Human Gene Array ST version 1.0 was performed in a total of 221 bronchial biopsies that were available from 90 COPD patients at baseline and after 6 and 30 months of therapy. Linear mixed effects modeling was used to analyze treatment-specific changes in gene expression. A validation set was included and pathway analysis was performed with Gene Set Enrichment Analysis (GSEA). Results: The expression of 138 genes significantly decreased after both 6 and 30 months of treatment with fluticasone ± salmeterol versus placebo, whereas the expression of 140 genes increased. A more pronounced treatment-induced change in expression of 51 of these 278 genes was associated with a slower rate of decline in FEV1. Genes that decreased with treatment were involved in pathways related to cell cycle, oxidative phosphorylation, epithelial cell signaling, p53 signaling and T cell signaling. Genes that increased with treatment were involved in pathways related to focal adhesion, gap junction and extracellular matrix deposition. Conclusion: The present study suggests that gene expression in biological pathways of COPD is dynamic with treatment and reflects disease activity. This study opens the gate to targeted and phenotype-driven therapy of COPD. First, a total of 162 samples were analysed (RNA derived from bronchial biopsies from COPD patients before and after treatment with fluticasone +/- salmeterol or placebo [GLUCOLD study]), 107 samples before and after 6 and 30 months of treatment with fluticasone +/- salmeterol and 55 samples before and after treatment with placebo. A total of 278 genes were found that changed in expression after both 6 and 30 months of treatment with fluticasone +/- salmeterol versus placebo. Next, an additional number of 59 samples from the fouth GLUCOLD treatment were put on array. In this study arm, COPD patients were treated for 6 months with fluticasone and then fluticasone was discontinued and patients switched to placebo for the remaining 24 months of the study.

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The effects of inhaled corticosteroids on healthy airways

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