University of Groningen Chronic mucus hypersecretion in COPD and asthma Tasena, Hataitip IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2019 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Tasena, H. (2019). Chronic mucus hypersecretion in COPD and asthma: Involvement of microRNAs and stromal cell-epithelium crosstalk. University of Groningen. Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). 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Download date: 06-10-2021 Chronic mucus hypersecretion in COPD and asthma: Involvement of microRNAs and stromal cell-epithelium crosstalk Hataitip Tasena 531891-L-bw-Tasena Processed on: 6-6-2019 PDF page: 1 The studies presented in this thesis were performed within the framework of the Groningen University Institute for Drug Exploration (GUIDE), the Groningen Research Institute for Asthma and COPD (GRIAC), and U4 Ageing Lung Consortium. They are financially supported by the University of Groningen, Stichting Astma Bestrijding (SAB), and de Cock foundation. Printing of this thesis was financially supported by the University of Groningen, the Graduate school of Medical Sciences Groningen (GSMS), and Stichting Astma Bestrijding (SAB). ISBN (printed): 978-94-034-1704-2 ISBN (electronic): 978-94-034-1703-5 Cover design by Nick (fiverr.com/glitchfool) Lay out by Abubakar Abdullahi Dubagari and Hataitip Tasena Printed by Ipskamp Printing, Enschede © 2019, Hataitip Tasena, The Netherlands All rights reserved. No part of this thesis may be reproduced or transmitted in any form or by any means without prior permission of the author or, when appropriate, of the publisher of the publication. 531891-L-bw-Tasena Processed on: 6-6-2019 PDF page: 2 Chronic mucus hypersecretion in COPD and asthma: Involvement of microRNAs and stromal cell-epithelium crosstalk PhD thesis to obtain the degree of PhD at the University of Groningen on the authority of the Rector Magnificus prof. E. Sterken and in accordance with the decision by the College of Deans. This thesis will be defended in public on Wednesday 3 July 2019 at 12.45 hours by Hataitip Tasena born on 23 April 1989 in Chiang Rai, Thailand 531891-L-bw-Tasena Processed on: 6-6-2019 PDF page: 3 Supervisors Prof. H.I. Heijink Prof. W. Timens Co-supervisors Dr. C.A. Brandsma Dr. M. van den Berge Assessment Committee Prof. K. Bracke Prof. G.H. Koppelman Prof. A. van den Berg 531891-L-bw-Tasena Processed on: 6-6-2019 PDF page: 4 Paranimfen Jennie Ong Roderick de Hilster 531891-L-bw-Tasena Processed on: 6-6-2019 PDF page: 5 In memory of my mom, Ketsuda. 531891-L-bw-Tasena Processed on: 6-6-2019 PDF page: 6 CONTENTS CHAPTER 1 General introduction 9 CHAPTER 2 Role of microRNAs and exosomes in asthma 21 Opin Pulm Med 2019: 25(1):87-93 CHAPTER 3 MicroRNA-mRNA regulatory networks underlying 33 chronic mucus hypersecretion in COPD Eur Respir J 2018: 52(3): 1701556 CHAPTER 4 MiR-31-5p: a shared regulator of chronic 71 mucus hypersecretion in asthma and chronic obstructive pulmonary disease CHAPTER 5 Airway mucus secretion in COPD-derived 87 airway epithelial cells is promoted by fibroblast-epithelium crosstalk CHAPTER 6 Involvement of miRNAs associated with chronic 109 mucus hypersecretion in fibroblast-epithelium crosstalk in COPD CHAPTER 7 MiR-146a-5p plays an essential role in the aberrant 119 epithelial-fibroblast crosstalk in COPD Eur Respir J 2017: 49(5): 1602538 CHAPTER 8 Profiling of healthy and asthmatic airway smooth 141 muscle cells following IL-1β treatment: a novel role for CCL20 in chronic mucus hypersecretion Eur Respir J 2018: 52(2): 1800310 CHAPTER 9 Summary, general discussion and future perspectives 171 CHAPTER 10 Dutch summary | Nederlandse samenvatting 187 CHAPTER 11 Acknowledgements | Dankwoord 193 APPENDIX Curriculum vitae and list of publications 209 531891-L-bw-Tasena Processed on: 6-6-2019 PDF page: 7 531891-L-bw-Tasena Processed on: 6-6-2019 PDF page: 8 CHAPTER 1 General introduction 531891-L-bw-Tasena Processed on: 6-6-2019 PDF page: 9 CHAPTER 1 Chronic mucus hypersecretion (CMH) is a feature observed in various chronic respiratory diseases, particularly chronic obstructive pulmonary disease (COPD)1,2 and asthma3,4. While COPD is one of the top leading causes of death worldwide especially in elderly5, asthma is the most common chronic disease among children6 and responsible for more than 400,000 deaths overall each year worldwide7. Both genetic and environmental factors contribute to COPD and asthma8–10, and cigarette smoke is widely recognized as a major cause of COPD10. COPD and asthma patients may experience similar symptoms, e.g. breathing difficulty, chest tightness, wheezing, and cough; however, these symptoms are driven by different—though partly overlapping—mechanisms11. In COPD, exposure to air pollutants or irritant particles (e.g. cigarette or wood smoke) triggers inflammatory responses characterized by infiltration of neutrophils, macrophages, T lymphocytes and innate lymphoid cells, which in the long-term causes damage to the lung12. Abnormal tissue repair is a key pathophysiological feature of COPD which leads to small airway wall thickening and/or destruction of alveolar tissue (emphysema)13, resulting in airflow limitation that is not fully reversible and accelerated lung function decline13,14. In asthma, the most common type is allergen-induced asthma characterized by chronic eosinophilic airway inflammation, airway remodeling with increased smooth muscle mass, subepithelial fibrosis and goblet cell hyperplasia14,15. In patients with allergic asthma, allergen-specific type-2 T-helper cells drive the airway inflammatory response that gives rise to clinical symptoms such as wheezing, variable airflow limitation and airway hyperresponsiveness16. As both are highly heterogeneous diseases, COPD and asthma patients can be categorized into different subgroups based on their clinical features. One of the important features shared by both COPD and asthma patients is CMH. CMH in COPD is often referred to as chronic bronchitis1,2. Here, it is associated with lower quality of life, an accelerated decline of lung function, more severe airflow obstruction and an increased risk of exacerbations and mortality17. In asthma, CMH is most prevalent in patients with severe asthma4 and associated with acute exacerbations18. Mucus plugging in the airways is found in the vast majority of fatal asthma cases and may be an important, but underappreciated, cause of respiratory failure19. Although some anti-inflammatory drugs, bronchodilators and antibiotics have been reported to reduce mucus production or improve mucus clearance, the results of the studies were either inconsistent or not yet proven to be beneficial in humans20. The lack of effective CMH-targeted therapy, while it represents a high burden, reflects an urgent need to better understand mechanisms underlying CMH pathophysiology in order to find better treatment options. 10 531891-L-bw-Tasena Processed on: 6-6-2019 PDF page: 10 General introduction Factors contributing to chronic mucus hypersecretion Patients with CMH suffer from chronic cough and sputum expectoration as a result of increased mucus accumulation in their airways, a process attributed to exaggerated 1 mucin secretion and/or impaired mucus clearance21. Increased mucin secretion in COPD and asthmatic airways likely results from increased numbers of goblet cells22–24 and enlargement of mucous glands25,26, increased mucin synthesis24,27–30 and/or increased degranulation of goblet cells31,32. Ineffective mucus clearance can be driven by defective cilia function33,34, changes in mucus composition35, mucus dehydration36 and/or higher viscoelasticity resulting from more mucin cross-linking or impaired mucin degradation37–39. All these factors are commonly used as markers for studying CMH, as summarized in figure 1. Mucins are heavily glycosylated proteins responsible for mucus viscoelasticity40. MUC5AC and MUC5B are the most common mucins present in the respiratory tract and they are associated with both COPD29,30 and asthma27,28. When external pathogens or noxious particles are inhaled, the airway epithelium is the first line of defense protecting the lungs from these harmful stimuli. It is composed of various epithelial cell types including basal cells and more differentiated cells, e.g. club cells, goblet cells and ciliated cells41. Mucins are synthesized by goblet cells as a constituent of the airway epithelium and by mucous cells in submucosal glands21. After being synthesized, mucins are stored in intracellular granules before being released into the airway lumen. Here, secreted mucins are mixed with lipids, antimicrobial proteins, electrolytes, and water to form a mucus layer40, which can then be transported from distal to proximal airways by the rhythmic beating of cilia before entering the larynx and being expectorated by a sudden opening of vocal cords42. Mucus which is accumulated in the airways requires effective clearance, a process that is often impaired in patients with COPD or asthma33,34,43. As described above, one of the factors contributing to ineffective mucus clearance is ciliary dysfunction.