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View of Respiratory Disease 145, 669–674 (1992)

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View of Respiratory Disease 145, 669–674 (1992) Allergen-induced chemokine release from the bronchial epithelium: A novel lysosomal release mechanism A dissertation submitted to the University of Cincinnati In partial fulfillment of the requirements for the degree of Doctor of Philosophy (Ph.D.) In the graduate program of Immunobiology Of the College of Medicine 2013 By Mark Webb B.S., Brigham Young University, 2007 Committee members Chair: Simon P. Hogan, Ph.D. Marshall Montrose, Ph.D. Lee Denson, M.D. Nives Zimmermann, M.D. Marsha Wills-Karp, Ph.D. Abstract Asthma is a chronic inflammatory disease of the lung. In recent years, the airway epithelium has been identified as an important contributor to the initial development of asthma after allergen exposure. The mechanisms by which epithelial cells respond to allergen to help drive downstream inflammation and the initiation of an immune response are poorly understood. In this dissertation we sought to understand the basic mechanisms that control release of chemokines and cytokines in general and CCL20 in particular. To do this, we measured levels of CCL20 and other cell mediators retained in cells and released from cells, and we visualized these mediators' intracellular localization via immunofluorescence microscopy. We found that a number of chemokines and cytokines are stored within bronchial epithelial cells under homeostatic conditions. In addition, CCL20 was stored in lysosomes, and its release was partially mediated through secretion of these lysosomes. In order to determine the intracellular localization of multiple chemokines and cytokines simultaneously, we again employed fluorescence microscopy. We also developed a novel technique to measure specific proteins in subcellular organelles using modified flow cytometry. We found that lysosomes containing CCL20 are released after exposure to HDM. We also found that the secretory lysosomes containing CCL20 also appear to contain other chemokines and cytokines released in response to HDM. We also found that allergens other than HDM induce release of specific subsets of chemokines and cytokines. These studies demonstrate a complex storage and release mechanism for chemokines and cytokines of the bronchial epithelium. These findings improve our understanding of the initial interactions between allergen and the epithelium, and provide i an interesting potential target for future treatments that will allow them to be both targeted and robust. ii Acknowledgments I would like to thank my advisor, Dr. Marsha Wills-Karp for her time and effort in helping me refine my scientific understanding. In addition, she provided a lab staffed with excellent post- doctoral fellows and graduate students who have also impacted me tremendously as I completed my degree. In particular, Stephane Lajoie, Stacey Burgess, and Ian Lewkowich have always provided a listening ear and sound opinions about specific hypotheses as needed. Their insights proved valuable as I sought to uncover the mechanisms presented herein. I would also like to thank my wife for her support and encouragement throughout the dissertation-writing process. iii Table of Contents ABSTRACT ............................................................................................................................................................... I ACKNOWLEDGMENTS ........................................................................................................................................... III TABLE OF CONTENTS ............................................................................................................................................. IV LIST OF ABBREVIATIONS ........................................................................................................................................ V CHAPTER 1 – GENERAL INTRODUCTION ................................................................................................................. 1 CHAPTER 2 – MECHANISM OF CCL20 RAPID RELEASE FROM ALLERGEN-EXPOSED EPITHELIAL CELLS ................... 56 CHAPTER 3 – SIGNALING PATHWAYS LEADING TO HDM-INDUCED CCL20 RELEASE FROM THE BRONCHIAL EPITHELIUM ......................................................................................................................................................... 93 CHAPTER 4 – ALLERGEN-INDUCED RELEASE OF MANY PREFORMED CHEMOKINES AND CYTOKINES IS THROUGH SECRETORY LYSOSOMES .................................................................................................................................... 139 CHAPTER 5 – SUMMARY AND DISCUSSION ........................................................................................................ 194 iv List of abbreviations AHR Airway hyperresponsiveness APTI Airway pressure time index ATP Adenosine triphosphate AUB Ambient urban Baltimore particulate matter BAL Bronchoalveolar lavage BLAST Basic local alignment search tool CCL C-C chemokine ligand CCR C-C chemokine receptor CFTR Cystic fibrosis transmembrane conductance receptor COX Cyclooxygenase CXCL C-X-C chemokine ligand CXCR C-X-C chemokine receptor DC Dendritic cell ELISA Enzyme-linked immunosorbent assay ENaC Epithelial sodium channel ERK Extracellular signal-relgulated kinase FBS Fetal bovine serum FGF Fibroblast growth factor GM-CSF Granulocyte-macrophage colony stimulating factor HDM House dust mite HS Heparan sulfate HSPG Heparan sulfate proteoglycan IL Interleukin ILC Innate lymphoid cells i.t. intra trachea JNK c-Jun N-terminal kinase LAMP Lysosome associated membrane protein LD50 Median lethal dose LPS Lipopolysachharride mTEC Mouse tracheal epithelial cell NHBE Normal human bronchial epithelial cell NKCC Na-K-Cl cotransporter NLRP3 NOD-like receptor family, pyrin domain containing 3 NSAID Non-steroidal anti-inflammatory drug PAMP Pathogen-associated molecular pattern PBS Phosphate-buffered saline pH Potential of hydrogen (measure of acidity) PKC Protein kinase C PNS Post-nuclear supernatant PRR Pattern recognition receptor RAB Ras-related protein v ROS Reactive oxygen species SOFA Single organelle fluorescence analysis SYK Spleen tyrosine kinase TCR T-cell receptor TGF-β Transforming growth factor beta TH Helper T-cell TNF-α Tumor necrosis factor alpha TSLP Thymic stromal lymphopoietin V-ATPase Vacuolar-type H+ adenosine triphosphatase Common Ions Ca2+ Calcium ion Cl- Chloride ion K+ Potassium ion Mg2+ Magnesium ion Na+ Sodium ion 3- PO4 Phosphate ion 2- SO4 Sulfate ion vi CHAPTER 1 – GENERAL INTRODUCTION ASTHMA .................................................................................................................................................................... 2 SYMPTOMS AND TREATMENT ................................................................................................................................... 2 INCIDENCE AND COSTS ............................................................................................................................................. 3 ETIOLOGY .................................................................................................................................................................. 4 MAJOR ALLERGENS ASSOCIATED WITH ALLERGIC ASTHMA .................................................................................... 7 PHYSIOLOGICAL CHANGES IN ASTHMATIC LUNGS ................................................................................................ 10 CELLULAR AND MOLECULAR MECHANISMS OF DISEASE .................................................................. 12 ALLERGIC ASTHMA IS MEDIATED BY TYPE -2 CELLS ................................................................................................ 13 DEVELOPMENT OF A TH2 RESPONSE ....................................................................................................................... 16 Dendritic cells in asthma .................................................................................................................................... 17 THE BRONCHIAL EPITHELIUM IN ASTHMA ............................................................................................................. 20 Ion transport in bronchial epithelial cells ........................................................................................................... 21 The bronchial epithelium and immunity ............................................................................................................ 26 ROLE OF CHEMOKINES /CYTOKINES IN ALLERGIC ASTHMA .................................................................................... 27 Inflammatory chemokines ................................................................................................................................... 28 CCL20 ............................................................................................................................................................................. 28 Other inflammatory chemokines and cytokines ....................................................................................................... 31 Secretory lysosomes ...................................................................................................................................................... 33 Syndecans and heparin sulfate proteoglycans .......................................................................................................... 38 SUMMARY ............................................................................................................................................................... 40 REFERENCES
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