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Molecular Pharmacology

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Research ArticleArticle

Phosphodiesterase 4 Inhibitors Augment the Ability of Formoterol to Enhance Glucocorticoid-Dependent Gene Transcription in Human Airway Epithelial Cells: A Novel Mechanism for the Clinical Efficacy of Roflumilast in Severe Chronic Obstructive Pulmonary Disease

Thunicia Moodley, Sylvia M. Wilson, Taruna Joshi, Christopher F. Rider, Pawan Sharma, Dong Yan, Robert Newton and Mark A. Giembycz
Molecular Pharmacology April 2013, 83 (4) 894-906; DOI: https://doi.org/10.1124/mol.112.083493
Thunicia Moodley
Departments of Physiology and Pharmacology (T.M., S.M.W., T.J., P.S., D.Y., M.A.G.) and Cell Biology and Anatomy (C.F.R., R.N.), Airways Inflammation Research Group, Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
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Sylvia M. Wilson
Departments of Physiology and Pharmacology (T.M., S.M.W., T.J., P.S., D.Y., M.A.G.) and Cell Biology and Anatomy (C.F.R., R.N.), Airways Inflammation Research Group, Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
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Taruna Joshi
Departments of Physiology and Pharmacology (T.M., S.M.W., T.J., P.S., D.Y., M.A.G.) and Cell Biology and Anatomy (C.F.R., R.N.), Airways Inflammation Research Group, Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
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Christopher F. Rider
Departments of Physiology and Pharmacology (T.M., S.M.W., T.J., P.S., D.Y., M.A.G.) and Cell Biology and Anatomy (C.F.R., R.N.), Airways Inflammation Research Group, Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
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Pawan Sharma
Departments of Physiology and Pharmacology (T.M., S.M.W., T.J., P.S., D.Y., M.A.G.) and Cell Biology and Anatomy (C.F.R., R.N.), Airways Inflammation Research Group, Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
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Dong Yan
Departments of Physiology and Pharmacology (T.M., S.M.W., T.J., P.S., D.Y., M.A.G.) and Cell Biology and Anatomy (C.F.R., R.N.), Airways Inflammation Research Group, Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
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Robert Newton
Departments of Physiology and Pharmacology (T.M., S.M.W., T.J., P.S., D.Y., M.A.G.) and Cell Biology and Anatomy (C.F.R., R.N.), Airways Inflammation Research Group, Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
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Mark A. Giembycz
Departments of Physiology and Pharmacology (T.M., S.M.W., T.J., P.S., D.Y., M.A.G.) and Cell Biology and Anatomy (C.F.R., R.N.), Airways Inflammation Research Group, Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
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Abstract

Post-hoc analysis of two phase III clinical studies found that the phosphodiesterase 4 (PDE4) inhibitor, roflumilast, reduced exacerbation frequency in patients with severe chronic obstructive pulmonary disease (COPD) who were taking inhaled corticosteroids (ICS) concomitantly, whereas patients not taking ICS derived no such benefit. In contrast, in two different trials also performed in patients with severe COPD, roflumilast reduced exacerbation rates in the absence of ICS, indicating that PDE4 inhibition alone is sufficient for therapeutic activity to be realized. Given that roflumilast is recommended as an “add-on” medication to patients with severe disease who will inevitably be taking a long-acting β2-adrenoceptor agonist (LABA)/ICS combination therapy, we tested the hypothesis that roflumilast augments the ability of glucocorticoids to induce genes with anti-inflammatory activity. Using a glucocorticoid response element (GRE) luciferase reporter transfected into human airway epithelial cells [both bronchial epithelium + adenovirus 12 - SV40 hybrid (BEAS-2B) cells and primary cultures], roflumilast enhanced fluticasone propionate–induced GRE-dependent transcription. Roflumilast also produced a sinistral displacement of the concentration-response curves that described the augmentation of GRE-dependent transcription by the LABA formoterol. In BEAS-2B cells and primary airway epithelia, roflumilast interacted with formoterol in a positive cooperative manner to enhance the expression of several glucocorticoid-inducible genes that have anti-inflammatory potential. We suggest that the ability of roflumilast and formoterol to interact in this way supports the concept that these drugs together may impart clinical benefit beyond that achievable by an ICS alone, a PDE4 inhibitor alone, or an ICS/LABA combination therapy. Roflumilast may, therefore, be especially effective in patients with severe COPD.

Footnotes

  • This study was supported by the Canadian Institutes for Health Research [MOP 93742]; the Lung Association, Alberta and Northwest Territories, Canada; and an unrestricted research grant from Nycomed Inc, USA.

  • dx.doi.org/10.1124/mol.112.083493.

  • Received November 6, 2012.
  • Accepted February 5, 2013.
  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 83 (4)
Molecular Pharmacology
Vol. 83, Issue 4
1 Apr 2013
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Research ArticleArticle

Roflumilast, GRE-Dependent Transcription, and Severe COPD

Thunicia Moodley, Sylvia M. Wilson, Taruna Joshi, Christopher F. Rider, Pawan Sharma, Dong Yan, Robert Newton and Mark A. Giembycz
Molecular Pharmacology April 1, 2013, 83 (4) 894-906; DOI: https://doi.org/10.1124/mol.112.083493

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Research ArticleArticle

Roflumilast, GRE-Dependent Transcription, and Severe COPD

Thunicia Moodley, Sylvia M. Wilson, Taruna Joshi, Christopher F. Rider, Pawan Sharma, Dong Yan, Robert Newton and Mark A. Giembycz
Molecular Pharmacology April 1, 2013, 83 (4) 894-906; DOI: https://doi.org/10.1124/mol.112.083493
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