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Molecular Pharmacology

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Transcriptome-level interactions between budesonide and formoterol provide insight into the mechanism of action of ICS/LABA combination therapy in asthma

Mahmoud M Mostafa, Christopher F. Rider, N Dulmini Wathugala, Richard Leigh, Mark A. Giembycz and Robert Newton
Molecular Pharmacology December 29, 2020, MOLPHARM-AR-2020-000146; DOI: https://doi.org/10.1124/molpharm.120.000146
Mahmoud M Mostafa
1Physiology & Pharmacology, University of Calgary, Canada
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Christopher F. Rider
2Medicine, University of British Columbia, Canada
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N Dulmini Wathugala
1Physiology & Pharmacology, University of Calgary, Canada
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Richard Leigh
3Department of Medicine, University of Calgary, Canada
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Mark A. Giembycz
4Physiology and Pharmacology, University of Calgary, Canada
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Robert Newton
4Physiology and Pharmacology, University of Calgary, Canada
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  • For correspondence: rnewton@ucalgary.ca
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Abstract

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 hypothesised 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 (1-2h) upregulated transcripts. Conversely, budesonide induced 370 and repressed 413 mRNAs, which occurred predominantly at 6-18h and were preceded by transcripts enriched in transcriptional regulators. Significantly, genes regulated by both formoterol and budesonide were overrepresented in the genome; moreover, budesonide-plus-formoterol induced and repressed 609 and 577 mRNAs, respectively, of which ~1/3 failed the cut-off criterion for either treatment alone. While 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 pro-inflammatory 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 presence of formoterol. Thus, LABAs modulate glucocorticoid action and comparable transcriptome-wide interactions in pHBECs imply that such effects may be extrapolated to asthmatics taking combination therapy. While repression of formoterol-induced pro-inflammatory mRNAs should be beneficial, the pathophysiological consequences of other interactions require investigation.

Significance Statement In human bronchial epithelial cells, formoterol, a long-acting β2-adrenoceptor agonist 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.

  • asthma
  • beta-adrenergic receptors
  • epithelial cells
  • glucocorticoids
  • Copyright © 2020 American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 99 (2)
Molecular Pharmacology
Vol. 99, Issue 2
1 Feb 2021
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Transcriptome-level glucocorticoid/LABA interactions

Mahmoud M Mostafa, Christopher F. Rider, N Dulmini Wathugala, Richard Leigh, Mark A. Giembycz and Robert Newton
Molecular Pharmacology December 29, 2020, MOLPHARM-AR-2020-000146; DOI: https://doi.org/10.1124/molpharm.120.000146

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OtherArticle

Transcriptome-level glucocorticoid/LABA interactions

Mahmoud M Mostafa, Christopher F. Rider, N Dulmini Wathugala, Richard Leigh, Mark A. Giembycz and Robert Newton
Molecular Pharmacology December 29, 2020, MOLPHARM-AR-2020-000146; DOI: https://doi.org/10.1124/molpharm.120.000146
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