The Effect of Phosphodiesterase Inhibitors on the Induction of Gene Expression by Long-Acting beta2-Adrenoceptor Agonists and Glucocorticoids

Recently, phosphodiesterases (PDE)4 inhibitors have received approval as a complementary anti-inflammatory treatment for chronic obstructive pulmonary disease (COPD) patients who are already taking long-acting β2-agonists (LABA)/inhaled corticosteroid (ICS) combination therapy. However, this benefit is seen only in patients of the severe, bronchitic, frequent exacerbator phenotype. Several strategies have been proposed to enhance the clinical efficacy of PDE4 inhibitors. One of these is the use of dual PDE3/4 inhibitors, which in addition to providing superior anti-inflammatory activity when compared to a PDE4 inhibitor alone, will also promote bronchodilatation. The present study demonstrates that a PDE3 plus a PDE4 inhibitor successfully sensitized BEAS-2B airway epithelial cells transfected with a cyclic adenosine 3',5'-monophosphate (cAMP)-response element luciferase reporter to the LABA, formoterol. Furthermore, PDE3 plus PDE4 inhibitors in combination prolonged and/or sensitized the ability of formoterol to induce several genes in BEAS-2B cells that have anti-inflammatory potential in the absence and presence of the glucocorticoid, dexamethasone. Collectively, these data suggest that LABA/ICS combination therapy in conjunction with an inhibitors of PDE3 and PDE4 may together improve clinical outcomes in larger a population of severe COPD patients.

Name thesis:degree_name

Master of Science (MSc)

Discipline thesis:degree_discipline

Medical Science

Grantor dc:publisher.institution

Graduate Studies

Year dc:date.issued

2013

Author dc:creator

• BinMahfouz, Hawazen

Advisors dc:contributor.advisor

• Newton, Robert
• Giembycz, Mark

• Molecular

Statement dc:rights

• University of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission.

Language dc:language.iso

eng

DOI

http://dx.doi.org/10.11575/PRISM/28088

OAI identifier oai:identifier

oai:ucalgary.scholaris.ca:11023/964