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An Investigation Into the Role of the Ion Channel Trpv4 in the Activation of Airway Sensory Nerves and the Cough Reflex

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An Investigation Into the Role of the Ion Channel Trpv4 in the Activation of Airway Sensory Nerves and the Cough Reflex AN INVESTIGATION INTO THE ROLE OF THE ION CHANNEL TRPV4 IN THE ACTIVATION OF AIRWAY SENSORY NERVES AND THE COUGH REFLEX Sara Jane Bonvini 2015 A thesis submitted for the Degree of Doctor of Philosophy in the Faculty of Medicine, Imperial College London Respiratory Pharmacology Group National Heart and Lung Institute Faculty of Medicine Imperial College London Sir Alexander Fleming Building Exhibition Road London SW7 2AZ Thesis Abstract The TRPV4 channel is a member of the Transient Receptor Potential family of ion channels and is known to be expressed on airway smooth muscle, macrophages and epithelial cells within the lung. Whilst it has been reported that TRPV4 is present on sensory nerves, its role in modulating the function of airway sensory nerves and the cough reflex remains unexplored. The aim of this thesis was therefore to determine a role for TRPV4 in sensory nerve activity and the cough reflex. Using an in vitro model of vagal sensory nerve activation and an in vivo guinea pig cough model, it was established that activation of TRPV4 by selective ligands activates airway sensory nerves and cause cough. Calcium imaging of isolated neurons and airway single fibre recordings determined that this was through activation of a different population of nerve fibres than those activated by TRPV1 and TRPA1 ligands, which are both known to activate sensory nerves and cause cough. Calcium flux and fibre firing demonstrated a delay prior to activation by a TRPV4 agonist, suggesting an indirect mechanism of action. Activation of TRPV4 has been linked to ATP release in several cell types, and therefore it was hypothesised that activation of TRPV4 on the nerves leads to ATP release and subsequently activation of airway sensory nerves. The purine receptor P2X3, which is activated by ATP, is expressed on airway sensory nerves, and a selective P2X1/3 agonist caused depolarisation of the vagus nerve and firing of Aδ single fibres in vivo. Further, TRPV4 induced activation of sensory nerves in vitro and cough in vivo was inhibited following the administration of a selective P2X3 antagonist. This data would suggest that the activation of airway sensory nerves by TRPV4 ligands causes ATP release which then activates P2X3 possibly present on the same subset of sensory nerves, to cause cough. The work within my thesis has therefore uncovered TRPV4 as a modulator of airway sensory nerves and associated functions such as cough, which exerts its actions via a novel mechanism of action and as such is a good candidate for possible anti- tussive therapies. 2 Acknowledgements First and foremost I would like to thank my supervisors Dr Mark Birrell and Professor Maria Belvisi for their support, guidance, encouragement and scientific expertise offered throughout my PhD. I am extremely grateful to them both for making my PhD a challenging yet rewarding and thoroughly enjoyable experience. I would also like to thank the NHLI for funding my studentship. My thanks also go to the Respiratory Pharmacology group past and present for their help, support, advice and friendship over the past 4 years, and of whom all have helped make my PhD a great experience. In no particular order I would like to thank Dr. Sarah Maher, Dr. Mike Wortley, Dr. Eric Dubuis, Katie Baker, Dr. Victoria Jones, Dr. Liang Yew-Booth, Dr. James Buckley, Dr. Megan Grace, Ryan Robinson, Dr Matt Baxter, Dr Nicole Dale, Bilel Dekkak and Abdel Dekkak. It has been a real pleasure working with all of you, and thank you all for making the PhD process so enjoyable. Special thanks also to Dr. John Adcock for his many hours carrying out single fibre experiments, and also for his careful proofreading of this thesis. I would also like to thank Dr Anthony Ford from Afferent Pharmaceuticals for the provision of the compound AF-353 used within this thesis. I would also like to thank my friends and family for their continued support and encouragement throughout the PhD process. To my gym buddies (Sarah, Victoria and Liang), and also to my PhD buddy Katie I would like to particularly thank for your friendship and for providing much needed stress-relief at times. Big thanks also to Frankie, Lorien, Amelia, Hayley and Bethia for your continuous encouragement and friendship throughout my PhD. To my family; Mum, Dad, Nicola, Josh and Jon thank you for your unconditional support, love and encouragement throughout this process. Last but certainly not least my love and thanks go to Nick for his unending patience, love and understanding throughout my PhD, and for never failing to make me smile. 3 Statement of Originality The work contained in this thesis is my own work, except where otherwise indicated and referenced appropriately. The concentration response to GSK1016790a in the nodose ganglia (Chapter 3, Fig 3.2) was carried out by Ms Yee-Man Ching. The single fibre experiments carried out in Chapters 3, 4 and 5 were performed by Dr John Adcock, with my assistance. 4 Copyright Declaration The copyright of this thesis rests with the author and is made available under a Creative Commons Attribution Non-Commercial No Derivatives licence. Researchers are free to copy, distribute or transmit the thesis on the condition that they attribute it, that they do not use it for commercial purposes and that they do not alter, transform or build upon it. For any reuse or redistribution, researchers must make clear to others the licence terms of this work. 5 Table of Contents Thesis Abstract .................................................................................................................. 2 Acknowledgements ........................................................................................................... 3 Statement of Originality ..................................................................................................... 4 Copyright Declaration ........................................................................................................ 5 List of Figures .................................................................................................................. 10 List of Tables ................................................................................................................... 12 List of Abbreviations ........................................................................................................ 13 Chapter 1: Introduction ....................................................................................................... 15 1.1: Cough ....................................................................................................................... 16 1.1.1: Physiology of the cough reflex ............................................................................ 16 1.1.2: Prevalence of cough .......................................................................................... 17 1.2. Causes of Chronic Cough ......................................................................................... 17 1.2.1: Asthma ............................................................................................................... 17 1.2.2: COPD ................................................................................................................ 18 1.2.3: Unexplained Chronic Cough .............................................................................. 20 1.2.4: Current therapies ............................................................................................... 21 1.3. The Cough Reflex and Airway Sensory Nerves ........................................................ 22 1.3.1: Sensory nerves subtypes and cough ............................................................. 27 1.4 Assessment of the cough reflex ................................................................................. 32 1.4.1: Animal Models of Cough .................................................................................... 32 1.4.2: Clinical Assessment of Cough ............................................................................ 33 1.5: Ion channels implicated in the cough reflex ........................................................... 35 1.5.1: P2X3 receptors .................................................................................................. 35 1.5.2: Transient Receptor Potential family of ion channels ........................................... 37 1.6: Thesis plan ........................................................................................................... 48 Chapter 2: Methodology ..................................................................................................... 49 2.1 Introduction ........................................................................................................... 50 2.2 Human and animal tissue ...................................................................................... 50 2.3 KO mouse breeding and genotyping ..................................................................... 50 2.3.1: Genetically modified mouse breeding ................................................................. 50 2.3.1: Genotyping and PCR ......................................................................................... 51 2.4 Measurement of mRNA levels to assess gene expression .................................... 52 2.4.1: RNA extraction ................................................................................................... 52 6 2.4.2: cDNA synthesis .................................................................................................
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