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The Role of Adipokines in Obesity-Associated Asthma

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The Role of Adipokines in Obesity-Associated Asthma The role of adipokines in obesity-associated asthma By David Gibeon A thesis submitted to Imperial College London for the degree of Doctor of Philosophy in the Faculty of Medicine 2016 National Heart and Lung Institute Dovehouse Street, London SW3 6LY 1 Author’s declaration The following tests on patients were carried out by myself and nurses in the asthma clinic at the Royal Brompton Hospital: lung function measurements, exhaled nitric oxide (FENO) measurement, skin prick testing, methacholine provocation test (PC20), weight, height, waist/hip measurement, bioelectrical impedance analysis (BIA), and skin fold measurements. Fibreoptic bronchoscopies were performed by me and previous research fellows in the Airways Disease Section at the National Heart and Lung Institute (NHLI), Imperial College London. The experiments carried out in this PhD were carried out using the latest equipment available to me at the NHLI. The staining of bronchoalveolar lavage cytospins with Oil red O (Chapter 4) and the staining of endobronchial biopsies with perilipin (Chapter 5) was performed by Dr. Jie Zhu. The multiplex assay (Chapter 7) was performed by Dr. Christos Rossios. 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. Signed………………………………… David Gibeon 2 Abstract Obesity is a risk factor for the development of asthma and plays a role in disease control, severity and airway inflammation. The relationship between asthma and adiposity is multifactorial and incorporates in-utero conditions, genetic factors, comorbidities and inflammation secondary to excess adipose tissue. Adipocytes produce cytokines, termed adipokines, which play an important role in systemic inflammation and have been correlated to the development of asthma and disease severity. Retrospective analysis of trials using inhaled corticosteroids and an in vitro study using alveolar macrophages has associated obesity with corticosteroid insensitivity in asthma. The first part of this study looked at data taken from a large cohort of well- characterised severe asthmatics and compared patient demographics, disease characteristics, healthcare utilisation and medication according to body mass index (BMI). Lipid laden macrophages (LLMs) in bronchoalveolar lavage fluid (BALF) and perilipin as a marker of lipid droplets in endobronchial biopsies were analysed according to asthma severity and BMI. Finally, peripheral blood mononuclear cells (PBMCs) were used to study the effect of BMI on steroid sensitivity in patients with asthma using an in vitro model and the effects of adipokines (leptin, resistin and adiponectin) on the release of pro-inflammatory cytokines and corticosteroid response were assessed. Severe asthmatics are often overweight (29.3%) or obese (48.3%). Increasing BMI was associated with increasing medication use in terms of short-acting β2- agonist (SABA) use per day, nebulisers and oral corticosteroid requirements (both maintenance and short burst therapy). In addition, obese severe asthmatics reported greater gastro-oesophageal reflux disease (GORD) and were less likely to be in full 3 time employment due to their asthma. LLMs are more prevalent in subjects with GORD which may explain the higher lipid laden macrophage index (LLMI) score seen in severe compared to mild/moderate asthmatics. Perilipin was expressed in the airway epithelium and submucosa in approximately half the study population. Greater expression was seen in the submucosa of asthmatic subjects compared to healthy controls. However, no significant correlations were noted in terms of asthma severity or BMI. Leptin, resistin and adiponectin were pro-inflammatory, in terms of CXCL8 release from PBMCs taken from asthmatics and healthy controls. PBMCs taken from severe asthmatics were less responsive to steroid suppression. Adiponectin induced IL-6, IL-10, CCL2, CCL3 and TNF-α release from PBMCs taken from asthmatics and healthy controls and IFN-γ, IL-1RA, CCL2, CCL3 and TNF-α release was suppressed by dexamethasone. Adiponectin induced CCL2 release and demonstrated relative corticosteroid insensitivity at dexamethasone 10-7 M in the severe asthma group. In conclusion, obesity related severe asthma is associated with more symptoms, a significant societal impact and patients are at risk of the many deleterious side effects of corticosteroid use. Leptin, resistin and adiponectin are pro- inflammatory and adiponectin may play an important role in modulating corticosteroid sensitivity. 4 Acknowledgements I would like to express my special appreciation and thanks to my PhD supervisors Professor Kian Fan Chung and Dr. Pankaj K Bhavsar, for the opportunity they have given me. Your advice on both research and my career has been invaluable. I also want to thank Dr. Christos Rossios and Dr. Jie Zhu for their technical help and support. I would especially like to thank João Pedro Rocha and Charlotte Goward who worked tirelessly to help me during my time at the NHLI. I would like to thank all my colleagues of the department who shared the highs and lows of research life and supported me through my PhD. Particular thanks to Dr. Christos Rossios for his advice, jokes and regular coffee trips. Finally, I wish to thank all of my friends and family who have had to put up with my moaning and provided me with endless cups of tea and support. 5 Table of Contents Abstract ..................................................................................................................... 3 Acknowledgements .................................................................................................. 5 Table of Contents ..................................................................................................... 6 List of Tables .......................................................................................................... 12 List of Figures ........................................................................................................ 14 Abbreviations ......................................................................................................... 17 Chapter 1. Introduction .......................................................................................... 20 1.1 Asthma ........................................................................................................... 21 1.1.1 An increasing problem ........................................................................... 22 1.1.2 Severe asthma ........................................................................................ 23 1.2 Obesity ........................................................................................................... 24 1.2.1 Obesity in the UK .................................................................................... 25 1.2.2 The impact of obesity ............................................................................. 26 1.3 Asthma and obesity ...................................................................................... 27 1.3.1 Epidemiology .......................................................................................... 27 1.3.2 Associations between asthma and obesity .......................................... 28 1.3.3 Phenotyping asthma and obesity .......................................................... 29 1.3.4 Lung function in the obese .................................................................... 30 1.3.5 Bariatric surgery ..................................................................................... 32 1.4 Animal models of obesity and asthma ........................................................ 32 1.5 Adipocytes and inflammation ...................................................................... 34 1.5.1 Adipose tissue, inflammation and the role of adipokines ................... 34 1.5.2 Alveolar macrophages, obesity and asthma ........................................ 36 1.6 Obesity, inflammation and oxidative stress ............................................... 37 1.6.1 Obesity and corticosteroid insensitivity ............................................... 37 1.6.2 Obesity and oxidative stress ................................................................. 39 1.6.3 Adipocytes and inflammation ................................................................ 40 6 1.7 Adipokines: Leptin, adiponectin and resistin ............................................. 42 1.7.1 Leptin ....................................................................................................... 42 1.7.2 Leptin and asthma .................................................................................. 45 1.7.3 Adiponectin ............................................................................................. 47 1.7.4 Adiponectin isoforms ............................................................................. 47 1.7.5 Adiponectin receptors ............................................................................ 48 1.7.6 Adiponectin: cellular action ................................................................... 49 1.7.7 Adiponectin: in vivo studies .................................................................
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