BackgroundThe effects of inhaled corticosteroids (ICS) on healthy airways are poorly defined.ObjectivesTo 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.MethodsRandomized 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.ResultsICS 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.ConclusionsIn 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.

中文翻译：

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吸入皮质类固醇对健康气道的影响

背景吸入皮质类固醇 (ICS) 对健康气道的影响尚不清楚。目的描述 ICS 对健康气道基因表达的影响，不混淆疾病相关基因的变化和 ICS 反应性的疾病相关改变。方法随机开放对 30 名健康成年志愿者进行高剂量 ICS 治疗的标签支气管镜检查研究，按 2:1 的比例随机分配至 (i) 丙酸氟替卡松 500 mcg，每天 500 mcg，或 (ii) 不治疗，持续 4 周。实验室工作人员对分配情况不知情。通过免疫组织化学、大量 RNA 测序、DNA 甲基化阵列和宏基因组学对活检和刷检进行分析。结果 ICS 导致血液和固有层嗜酸性粒细胞数量存在较小的组间差异，但在其他免疫病理学特征、血液中性粒细胞、FeNO、FEV1 方面没有差异1、微生物组或 DNA 甲基化。 ICS治疗上调了刷检中的72个基因和活检中的53个基因，下调了刷检中的82个基因和活检中的416个基因。两种组织中下调最多的基因是 2 型炎症的典型标志物（FCER1A、CPA3、IL33、CLEC10A、SERPINB10 和 CCR5）、T 细胞介导的适应性免疫（TARP、TRBC1、TRBC2、PTPN22、TRAC、CD2、CD8A、 HLA-DQB2、CD96、PTPN7）、B 细胞免疫（CD20、免疫球蛋白重链和轻链）和先天免疫，包括 CD48、Hobit、RANTES、Langerin 和 GFI1。 ICS 不会上调 IL-17 依赖性基因特征。结论在健康气道中，暴露 4 周的 ICS 会降低与先天性和适应性免疫相关的基因表达，并减少 2 型炎症标志物。这意味着健康的体内平衡涉及气道粘膜中的强直 2 型信号传导，而气道粘膜对 ICS 非常敏感。