In 2019, the Global Initiative for Asthma treatment guidelines were updated to recommend that inhaled corticosteroid (ICS)/long-acting β₂-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.

中文翻译：

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布地奈德和福莫特罗之间的转录组水平相互作用为哮喘患者吸入皮质类固醇/长效β2-肾上腺素受体激动剂联合治疗的作用机理提供了见识。

在2019年，在全球哮喘治疗指南进行了更新建议吸入糖皮质激素（ICS）/长效β ₂肾上腺素能受体激动剂（LABA）联合治疗应成为哮喘的首选治疗方法。尽管临床上优于ICS，但尚不清楚该联合疗法疗效的潜在机制。我们假设存在转录组相互作用，该效应已在BEAS-2B和原代人支气管上皮细胞（pHBEC）中使用福莫特罗和布地奈德作为代表LABA和ICS进行了测试。在BEAS-2B细胞中，福莫特罗产生了267个基因表达（诱导的212个； 55个被抑制的）的基因表达变化（≥2/≤0.5倍），主要由快速（1至2小时）上调的转录本所控制。相反，布地奈德可诱导370个mRNA并抑制413个mRNA，这些mRNA主要发生在6-18小时，然后是富含转录调节因子的转录本。显着地，福莫特罗和布地奈德均调节的基因在基因组中过分表达。此外，布地奈德加福莫特罗分别诱导并抑制了609和577个mRNA，其中约有三分之一未通过单独治疗的临界值。尽管布地奈德加福莫特罗对许多mRNA的诱导是超加性的，但布地奈德对福莫特罗诱导的转录本（包括编码许多促炎蛋白的转录本）的显性（且可能是有益的）作用是抑制。布地奈德调节的转录组的基因本体分析返回了丰富的术语，用于转录，凋亡，增殖，分化，发育和迁移。在福莫特罗的存在下，这种“功能性” ICS签名得到了增强。因此，LABA调节糖皮质激素的作用，pHBECs中转录组范围的可比性相互作用和类似作用暗示，这种作用可能被推断为接受联合治疗的哮喘患者。尽管抑制福莫特罗诱导的促炎性mRNA应该是有益的，但其他相互作用的病理生理后果仍需调查。