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OtherInflammation, Immunopharmacology, and Asthma

Prostanoid receptors of the EP4-subtype mediate gene expression changes in human airway epithelial cells with potential anti-inflammatory activity

Radhika Joshi, Omar Hamed, Dong Yan, Aubrey N Michi, Mahmoud M Mostafa, Shahina Wiehler, Robert Newton and Mark A. Giembycz
Journal of Pharmacology and Experimental Therapeutics November 6, 2020, JPET-AR-2020-000196; DOI: https://doi.org/10.1124/jpet.120.000196
Radhika Joshi
1Physiology & Pharmacology, University of Calgary, Canada
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Omar Hamed
1Physiology & Pharmacology, University of Calgary, Canada
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Dong Yan
2Pfizer, United States of America
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Aubrey N Michi
1Physiology & Pharmacology, University of Calgary, Canada
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Mahmoud M Mostafa
1Physiology & Pharmacology, University of Calgary, Canada
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Shahina Wiehler
1Physiology & Pharmacology, University of Calgary, Canada
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Robert Newton
3Physiology and Pharmacology, University of Calgary, Canada
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Mark A. Giembycz
3Physiology and Pharmacology, University of Calgary, Canada
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  • For correspondence: giembycz@ucalgary.ca
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Abstract

There is a clear, unmet clinical need to identify new drugs to treat individuals with asthma, chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) in whom current medications are either inactive or sub-optimal. In preclincal models, EP4-receptor agonists display efficacy, but their mechanism of action is unclear. In this study, using human bronchial epithelial cells as a therapeutically-relevent drug target, we hypothesised that changes in gene expression may play an important role. Several prostanoid receptor mRNAs were detected in BEAS-2B cells, human primary bronchial epithelial cells (HBEC) grown in submersion culture and HBEC grown at an air-liquid interface (ALI) with PTGER4 predominating. By using the activation of a cAMP-response element reporter in BEAS-2B cells as a surrogate of gene expression, Schild analysis determined that PTGER4 mRNAs encoded functional EP4-receptors. Moreover, inhibitors of phosphodiesterase 4 (roflumilast N-oxide [RNO]) and cAMP-dependent protein kinase augmented and attenuated, respectively reporter activation induced by ONO-AE1-329, a selective EP4-receptor agonist. ONO-AE1-329 also enhanced dexamethasone-induced activation of a glucocorticoid-response element reporter in BEAS-2B cells, which was similarly potentiated by RNO. In each airway epithelial cell variant, numerous genes that may impart therapeutic benefit in asthma, COPD and/or IPF were differentially expressed by ONO-AE1-329, and those changes were often augmented by RNO and/or dexamethasone. We submit that an EP4-receptor agonist, either alone or as a combination therapy, may be beneficial in individuals with chronic lung diseases in whom current treatment options are inadequate.

Significance Statement Using human bronchial epithelial cells as a therapeutically-relevant drug target, we report that EP4-receptor activation promoted gene expression changes that could provide therapeutic benefit in individuals with asthma, chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis in whom current treatment options are ineffective or sub-optimal.

  • cAMP
  • epithelial cells
  • Prostanoid
  • respiratory pharmacology
  • Copyright © 2020 American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 376 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 376, Issue 2
1 Feb 2021
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OtherInflammation, Immunopharmacology, and Asthma

Genomic effects of EP4-receptor agonist in airway epithelia

Radhika Joshi, Omar Hamed, Dong Yan, Aubrey N Michi, Mahmoud M Mostafa, Shahina Wiehler, Robert Newton and Mark A. Giembycz
Journal of Pharmacology and Experimental Therapeutics November 6, 2020, JPET-AR-2020-000196; DOI: https://doi.org/10.1124/jpet.120.000196

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OtherInflammation, Immunopharmacology, and Asthma

Genomic effects of EP4-receptor agonist in airway epithelia

Radhika Joshi, Omar Hamed, Dong Yan, Aubrey N Michi, Mahmoud M Mostafa, Shahina Wiehler, Robert Newton and Mark A. Giembycz
Journal of Pharmacology and Experimental Therapeutics November 6, 2020, JPET-AR-2020-000196; DOI: https://doi.org/10.1124/jpet.120.000196
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