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The Effect of Phosphodiesterase Inhibitors on the Induction of Gene Expression by Long-Acting Beta2-Adrenoceptor Agonists and Glucocorticoids

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The Effect of Phosphodiesterase Inhibitors on the Induction of Gene Expression by Long-Acting Beta2-Adrenoceptor Agonists and Glucocorticoids University of Calgary PRISM: University of Calgary's Digital Repository Graduate Studies The Vault: Electronic Theses and Dissertations 2013-09-13 The Effect of Phosphodiesterase Inhibitors on the Induction of Gene Expression by Long-Acting beta2-Adrenoceptor Agonists and Glucocorticoids BinMahfouz, Hawazen BinMahfouz, H. (2013). The Effect of Phosphodiesterase Inhibitors on the Induction of Gene Expression by Long-Acting beta2-Adrenoceptor Agonists and Glucocorticoids (Unpublished master's thesis). University of Calgary, Calgary, AB. doi:10.11575/PRISM/28088 http://hdl.handle.net/11023/964 master thesis 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. Downloaded from PRISM: https://prism.ucalgary.ca UNIVERSITY OF CALGARY The Effect of Phosphodiesterase Inhibitors on the Induction of Gene Expression by Long-Acting beta2-Adrenoceptor Agonists and Glucocorticoids by Hawazen BinMahfouz A THESIS SUBMITTED TO THE FACULTY OF GRADUATE STUDIES IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE DEPARTMENT OF MEDICAL SCIENCES CALGARY, ALBERTA SEPTEMBER, 2013 © Hawazen BinMahfouz 2013 Abstract 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. ii Acknowledgements First and foremost, I want to thank God for allowing me to attain my current accomplishments and for enabling so many people to facilitate my Study. I would also like to express my sincere gratitude to my supervisors, Dr. Robert Newton and Dr. Mark A Giembycz, for their understanding, patience and continual assistance during my Master program. I also appreciate the contributions of my committee members, Dr. Kris Chadee and Dr. Stephen Field, for their kindness and patience throughout my thesis project. I am grateful for the members of the Newton/Giembycz Lab, Sylvia, Christopher, Elizabeth, Tresa, Suharsh, Taruna and Dong, who provided me with guidance throughout my investigations. A special thank goes to my father, my King, King Abdullah Bin-Abdulaziz, for his generous scholarship, and the Saudi Cultural Bureau for their support and assistance. Most importantly, I want to express my sincere appreciation for my parents, whose love has inspired me to accomplish so much. I give many thanks to my sisters, Amal and Nour, as well as to my brothers, Abdullah and Abdulelah, for all of their help with this journey. I want to recognize the tremendous support and help from my best friend, my sister, Rania Mufti. She has lessened my stress and provided me with friendship, always listening to me. Also, I want to give special thanks to Mahmoud El-Daly for his perpetual assistance. Finally, I am so grateful for the contributions that each and every one made in giving me both personal and academic assistance. iii List of Abbreviations AAT alpha-1 antitrypsin AC adenylyl cyclase Ad5 adenovirus serotype 5 AP-1 activator protein-1 ASM airway smooth muscle ATP adenosine triphosphate AU adenine–uracil BSA bovine serum albumin CaM calmodulin cAMP cyclic adenosine 3',5'-monophosphate CBP CREB-binding protein CD cluster of differentiation CD200 cluster of differentiation 200 CHMP committee for medicinal products for human use COPD chronic obstructive pulmonary disease CRE cAMP-response element CREB cAMP-response element-binding protein CRISPLD2 cysteine-rich secretory protein LCCL (limulus clotting factor C, cochlin, lgl1) domain-containing 2 CXCL CXC chemokine ligand CXCR2 CXC chemokine ligand 2 receptor DAG 1,2-diacylglycerol DMEM Dulbecco's modified eagle's medium EC50 half maximal effective concentration iv EDTA ethylenediaminetetraacetic acid EMEA European medicines agency Epac exchange proteins directly activated by cAMP ERK extracellular signal-regulated protein kinase FCS foetal calf serum FEV1 forced expiratory volume in one second FGF-2 fibroblast growth factor-2 FVC forced vital capacity GAP GTPase-activating protein GAPDH glyceraldehyde-3-phosphate dehydrogenase GDP guanosine diphosphate GILZ glucocorticoid-inducible leucine zipper GM-CSF granulocyte/macrophage colony-stimulating factor GOLD global initiative for chronic obstructive lung disease GPCR G-protein coupled receptor GR glucocorticoid receptor GRE glucocorticoid response element GRK G-protein receptor kinases GRO growth-related oncogene GTP guanosine triphosphate HAT histone acetyltransferase HBSS Hanks balanced salt solution HDAC histone deacetylase Hsp heat-shock protein ICAM intercellular adhesion molecules v ICS inhaled corticosteroid IFNγ interferon-γ IL interleukin IP3 inositol 1,4,5-trisphosphate IP3R inositol 1,4,5-trisphosphate receptor JNK c-Jun NH2-terminal kinases LABA long-acting β2-agonists LPS lipopolysaccharide M muscarinic receptors MAPK mitogen-activated protein kinases MKP-1 mitogen-activated protein kinase phosphatase-1 MLC myosin light chain MLCK myosin light chain kinase MLCP myosin light chain phosphatase MMP9 matrix metalloproteinase 9 MOI multiplicity of infection NF-κB nuclear factor κB nGRE negative glucocorticoid response element NK2 tachykinin neurokinin type 1 p57KIP2 kinase inhibitor protein 2 of 57kDa PAGE polyacrylamide gel electrophoresis PDE phosphodiesterases PEPCK phosphoenol pyruvate carboxykinase PGE2 prostaglandin E2 PIP2 phosphoinositol 4,5-bisphosphate vi PKA cyclic AMP-dependent protein kinase A PKB protein kinase B PKG cyclic GMP- dependent protein kinase PKI protein kinase A inhibitor PLA2 phospholipase A2 PLC phospholipase C RGS2 regulator of G-protein signalling 2 ROCK Rho-associated protein kinase SABA short-acting β2-adrenoceptor agonists Ser serine siRNA small interfering RNA SLPI secretory leucocyte protease inhibitor SOCS3 suppressor of cytokine signaling 3 SR sarcoplasmic reticulum Tc1 type 1 cytotoxic TGF transforming growth factor Th1 type 1 helper T cells TLR4 toll-like receptor 4 TNFα tumor necrosis factor-alpha TORCH Towards a revolution in COPD health VEGF vascular endothelial growth factor WHO World Health Organization vii Table of Contents Abstract ................................................................................................................. ii Acknowledgments ................................................................................................. iii List of Abbreviations .............................................................................................. iv Table of Contents .................................................................................................viii List of Tables .........................................................................................................xii List of Figures...................................................................................................... .xiii CHAPTER ONE: INTRODUCTION ........................................................................ 1 1.1 Chronic obstructive pulmonary disease ............................................................ 1 1.1.1 Definition and prevalence. ....................................................................... 1 1.1.2 Phenotypes of COPD .............................................................................. 2 1.1.3 Causes of COPD ..................................................................................... 2 1.2 Airways inflammation ....................................................................................... 3 1.3 COPD treatment ............................................................................................... 4 1.3.1 Bronchodilators in the treatment of COPD ............................................. 5 1.3.1.1 Anti-cholinergics .......................................................................... 5 A. Muscarinic receptors ............................................................. 5 B. Muscarinic receptor signalling ............................................... 6 1.3.1.2 β2-Adrenoceptor agonists ........................................................... 8 A. β2-Adrenoceptor agonists .....................................................
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