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Molecular Pharmacology

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Research ArticleArticle

Transcriptome-Level Interactions between Budesonide and Formoterol Provide Insight into the Mechanism of Action of Inhaled Corticosteroid/Long-Acting β2-Adrenoceptor Agonist Combination Therapy in Asthma

Mahmoud M. Mostafa, Christopher F. Rider, N. Dulmini Wathugala, Richard Leigh, Mark A. Giembycz and Robert Newton
Molecular Pharmacology March 2021, 99 (3) 197-216; DOI: https://doi.org/10.1124/molpharm.120.000146
Mahmoud M. Mostafa
Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
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Christopher F. Rider
Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
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N. Dulmini Wathugala
Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
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Richard Leigh
Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
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Mark A. Giembycz
Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
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Robert Newton
Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
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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 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 β2-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.

Footnotes

    • Received August 16, 2020.
    • Accepted December 7, 2020.
  • ↵1 Current affiliation: Respiratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.

  • This study was supported by Canadian Institutes for Health Research (CIHR) project grants [MOP 125918, PJT 156310] and by a Natural Sciences and Engineering Research Council (NSERC) Discovery Grant [RGPIN-2016-04549]. M.M.M. received NSERC Postgraduate Scholarship-Doctoral, Elizabeth II Doctoral scholarship, and The Lung Association – Alberta and Northwest Territories studentship awards. Real-time polymerase chain reaction (PCR) machines was facilitated by an equipment and infrastructure grant from the Canadian Foundation for Innovation and the Alberta Science and Research Authority.

  • https://doi.org/10.1124/molpharm.120.000146.

  • ↵Embedded ImageThis article has supplemental material available at molpharm.aspetjournals.org.

  • Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 99 (3)
Molecular Pharmacology
Vol. 99, Issue 3
1 Mar 2021
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Research ArticleArticle

Transcriptome-Level Glucocorticoid/LABA Interactions

Mahmoud M. Mostafa, Christopher F. Rider, N. Dulmini Wathugala, Richard Leigh, Mark A. Giembycz and Robert Newton
Molecular Pharmacology March 1, 2021, 99 (3) 197-216; DOI: https://doi.org/10.1124/molpharm.120.000146

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Research ArticleArticle

Transcriptome-Level Glucocorticoid/LABA Interactions

Mahmoud M. Mostafa, Christopher F. Rider, N. Dulmini Wathugala, Richard Leigh, Mark A. Giembycz and Robert Newton
Molecular Pharmacology March 1, 2021, 99 (3) 197-216; DOI: https://doi.org/10.1124/molpharm.120.000146
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