Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada.
Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
Mol Pharmacol. 2021 Mar;99(3):197-216. doi: 10.1124/molpharm.120.000146. Epub 2020 Dec 29.
In 2019, the Global Initiative for Asthma treatment guidelines were updated to recommend that inhaled corticosteroid (ICS)/long-acting -adrenoceptor agonist (LABA) combination therapy should be a first-in-line treatment option for asthma. Although clinically superior to ICS, mechanisms underlying the efficacy of this combination therapy remain unclear. We hypothesized the existence of transcriptomic interactions, an effect that was tested in BEAS-2B and primary human bronchial epithelial cells (pHBECs) using formoterol and budesonide as representative LABA and ICS, respectively. In BEAS-2B cells, formoterol produced 267 (212 induced; 55 repressed) gene expression changes (≥2/≤0.5-fold) that were dominated by rapidly (1 to 2 hours) upregulated transcripts. Conversely, budesonide induced 370 and repressed 413 mRNAs, which occurred predominantly at 6-18 hours and was preceded by transcripts enriched in transcriptional regulators. Significantly, genes regulated by both formoterol and budesonide were over-represented in the genome; moreover, budesonide plus formoterol induced and repressed 609 and 577 mRNAs, respectively, of which ∼one-third failed the cutoff criterion for either treatment alone. Although induction of many mRNAs by budesonide plus formoterol was supra-additive, the dominant (and potentially beneficial) effect of budesonide on formoterol-induced transcripts, including those encoding many proinflammatory proteins, was repression. Gene ontology analysis of the budesonide-modulated transcriptome returned enriched terms for transcription, apoptosis, proliferation, differentiation, development, and migration. This "functional" ICS signature was augmented in the presence of formoterol. Thus, LABAs modulate glucocorticoid action, and comparable transcriptome-wide interactions in pHBECs imply that such effects may be extrapolated to individuals with asthma taking combination therapy. Although repression of formoterol-induced proinflammatory mRNAs should be beneficial, the pathophysiological consequences of other interactions require investigation. SIGNIFICANCE STATEMENT: In human bronchial epithelial cells, formoterol, a long-acting -adrenoceptor agonist (LABA), enhanced the expression of inflammatory genes, and many of these changes were reduced by the glucocorticoid budesonide. Conversely, the ability of formoterol to enhance both gene induction and repression by budesonide provides mechanistic insight as to how adding a LABA to an inhaled corticosteroid may improve clinical outcomes in asthma.
在 2019 年，全球哮喘治疗倡议指南进行了更新，建议将吸入性皮质类固醇（ICS）/长效β-受体激动剂（LABA）联合治疗作为哮喘的一线治疗选择。尽管在临床上优于 ICS，但这种联合治疗的疗效机制仍不清楚。我们假设存在转录组相互作用，并用福莫特罗和布地奈德分别作为代表性的 LABA 和 ICS，在 BEAS-2B 和原代人支气管上皮细胞（pHBEC）中测试了这种效应。在 BEAS-2B 细胞中，福莫特罗产生了 267 个（212 个诱导；55 个抑制）基因表达变化（≥2/≤0.5 倍），这些变化主要由快速（1 至 2 小时）上调的转录本主导。相反，布地奈德诱导了 370 个和抑制了 413 个 mRNA，主要发生在 6-18 小时，之前是富含转录因子的转录本。显著的是，受福莫特罗和布地奈德共同调控的基因在基因组中过度表达；此外，布地奈德加福莫特罗分别诱导和抑制了 609 个和 577 个 mRNA，其中约三分之一不符合单独治疗的标准。尽管布地奈德加福莫特罗诱导许多 mRNA 的作用是超加性的，但布地奈德对福莫特罗诱导的转录本的主要（潜在有益）作用是抑制，包括那些编码许多促炎蛋白的转录本。对布地奈德调节的转录组进行的基因本体分析，返回了丰富的转录、凋亡、增殖、分化、发育和迁移术语。在存在福莫特罗的情况下，这种“功能性”ICS 特征得到了增强。因此，LABA 调节糖皮质激素的作用，而在 pHBEC 中类似的全转录组相互作用表明，这些作用可能被外推到接受联合治疗的哮喘患者。虽然抑制福莫特罗诱导的促炎 mRNA 应该是有益的，但其他相互作用的病理生理后果需要进一步研究。意义：在人支气管上皮细胞中，福莫特罗，一种长效β-肾上腺素能受体激动剂（LABA），增强了炎症基因的表达，而糖皮质激素布地奈德减少了许多这样的变化。相反，福莫特罗增强布地奈德对基因诱导和抑制的能力，为添加 LABA 到吸入性皮质类固醇可能如何改善哮喘的临床结果提供了机制上的见解。
