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Randomized Controlled Trial
. 2024 Jul;79(7):1831-1843.
doi: 10.1111/all.16146. Epub 2024 Apr 30.

The effects of inhaled corticosteroids on healthy airways

Emanuele Marchi  1 , Timothy S C Hinks  1 , Matthew Richardson  2 , Latifa Khalfaoui  2 , Fiona A Symon  2 , Poojitha Rajasekar  3 , Rachel Clifford  3 , Beverley Hargadon  2 , Cary D Austin  4 , Julia L MacIsaac  5 , Michael S Kobor  5 , Salman Siddiqui  2 , Jordan S Mar  4 , Joseph R Arron  4 , David F Choy  4 , Peter Bradding  2
Affiliations
Randomized Controlled Trial

The effects of inhaled corticosteroids on healthy airways

Emanuele Marchi et al. Allergy. 2024 Jul.

Abstract

Background: The effects of inhaled corticosteroids (ICS) on healthy airways are poorly defined.

Objectives: 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.

Methods: Randomized open-label bronchoscopy study of high-dose ICS therapy in 30 healthy adult volunteers randomized 2:1 to (i) fluticasone propionate 500 mcg bd daily or (ii) no treatment, for 4 weeks. Laboratory staff were blinded to allocation. Biopsies and brushings were analysed by immunohistochemistry, bulk RNA sequencing, DNA methylation array and metagenomics.

Results: ICS induced small between-group differences in blood and lamina propria eosinophil numbers, but not in other immunopathological features, blood neutrophils, FeNO, FEV1, microbiome or DNA methylation. 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.

Conclusions: 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.

Trial registration: ClinicalTrials.gov NCT02476825.

Keywords: asthma; bronchial biopsy; epigenetics; health; inhaled corticosteroids; microbiome; transcriptome.

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Conflict of interest statement

Author conflict of interest statement

EM-none.

TSCH - TSCH has received grants from Pfizer Inc., the University of Oxford, the Wellcome Trust, the Medical Research Council, Asthma UK+Lung, the NIHR Oxford Biomedical Research Centre, Sensyne Health, and Kymab during the conduct of the study; and personal fees from AZ Pieris, and Kymab outside the submitted work.

MR – none.

LK – none.

FAS – none.

PR – none.

RC – RC is supported by an Anne McLaren Fellowship.

BH-none.

CDA – CDA is an employee of Genentech.

JLM – none.

MSK – none.

SS – SS has received consulting fees and honoraria from AstraZeneca, GSK, Roche, CSL Behring, Chiesi, Areteia Therapeutics, ERT Medical, Medscape, European Respiratory Society.

JSM – JSM is an employee of Genentech.

JRA – JRA is a former employee of Genentech and named inventor on granted and pending patents related to asthma diagnosis and treatment.

DFC – DFC is an employee of Genentech, and is an inventor of filed and approved patents for the treatment and diagnosis of chronic lung diseases. As an employee of Genentech, DFC holds Roche shares and stock options.

PB - PB has received research funding from Genentech via the University Hospitals of Leicester NHS Trust; consultancy for Genentech via the University of Leicester. Support to attend scientific meetings from Chiesi, GSK and Sanofi-Regeneron, and one honorarium from AstraZeneca.

Figures

Figure 1
Figure 1
Immunohistochemical analysis of the lamina propria biopsies showing cell counts and remodelling features on participants with available paired data, before and after 4 weeks treatment with inhaled fluticasone or without treatment. The change in numbers of A) eosinophils, with atopic participants shown in red, B) tryptase-positive mast cells, C) chymase-positive mast cells, or D) neutrophils, expressed in absolute counts/mm2. Changes in area of E) epithelium or F) airway smooth muscle (ASM), expressed as a percentage of biopsy area or of G) reticular basement membrane (RBM) thickness. Horizontal bars represent mean (SD)(mast cells, neutrophils, ASM, epithelium, RBM) or median (IQR) (eosinophils), analysed by unpaired t test or Mann Whitney U respectively. Obs represents the observation group.
Figure 2
Figure 2
Changes in gene expression measured by RNAseq in response to 4 weeks treatment with inhaled fluticasone. Log2 fold changes and statistical tests calculated using moderated t tests on vsn normalized log2(count per million) values in Limma. A) Bronchial brush volcano plot. B) Bronchial biopsy volcano plot.
See this image and copyright information in PMC

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