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Functional Identification and Modeling of Nerves in Airways

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DISSERTATION APPROVED BY S+ LotY \,N Date Peter W. Abel, Ph.D., Chair --\- c... Tu, Ph.D Myron T Ph.D. C/,*-?¿tr z3o-ko,?r4 C ,/,+z¿¿î Z3 oc?t¿ m,r P¿'D , Gail M. J Ph.D., Dean FUNCTIONAL IDENTIFICATION AND MODELING OF NERVES IN AIRWAYS ___________________________ By CAMERON M. KIEFFER ___________________________ A DISSERTATION Submitted to the faculty of the Graduate School of Creighton University in Partial Fulfillment of the Requirements for the degree of Doctor of Philosophy in the Department of Pharmacology ___________________________ Omaha, NE August 20, 2018 ABSTRACT Constriction of mammalian airways is primarily driven by nerves that release the neurotransmitter acetylcholine (ACh). One FDA approved class of drugs blocks ACh- induced constriction in asthma. However, nerves contain other neurotransmitters that may also be targets for asthma treatment. To further characterize the role of various neurotransmitters in modulating airway constriction, nerves in isolated mouse airways were activated using electrical field stimulation (EFS) which causes release of neurotransmitters. Constriction and relaxation caused by neurotransmitters were pharmacologically blocked to decipher their roles in airway function. EFS caused an ACh-mediated constriction phase and a relaxation phase blocked by capsaicin and indomethacin. Drug distribution models build outward from first principles using computational methods to describe the movement of drugs in an organism. These models create a rigorous mathematical framework to allow for simulation of in vitro and in vivo processes. My hypothesis was that a computational drug distribution model can consolidate experimental data into a mathematical description of the functional role of nerves in mouse airways. Data from isolated trachea experiments informed the design of compartment-based computational models. By minimizing the sum of squares error, the computational models predicted kinetic parameters that described ACh-induced trachea constriction in response to EFS. Identifying the mediators of the relaxation phase that were eliminated by capsaicin and indomethacin was the second necessary step toward development of a complete functional model. Sensory neuropeptides and prostanoid receptors were iii pharmacologically blocked to decipher their roles in regulating airway relaxation. Results of experiments indicated that PGE2 is a candidate mediator of the EFS-induced relaxation phase. Therefore, the PGE2 receptor EP2 was incorporated into the drug distribution model. The updated Multiple Neurotransmitter model was able to reproduce biphasic EFS responses, consistent with experimental observations. This work contributes a novel perspective to the study of the functional neurotransmitter systems in the lung. Coupled with in vitro and in vivo experiments, a more complete model may aid in silico testing of drugs, furthering the development of new therapeutics for the treatment of asthma and other lung diseases. iv ACKNOWLEDGMENTS Of course, everything starts and ends with my parents Michael and Jean Kieffer. Thank you for raising me to be a curious child and supporting me in my crazy endeavors. From Boy Scouts, to Scholar Bowl, to college, and to graduate school, you have always been behind me pushing me forward. Thank you to Elliott and Melanie Kieffer too, for being great siblings. I love you all. Thank you to Nathaniel Ray Rosol, Julia Chowdhury, and Amy Tu who all worked in Dr. Abel’s Lab and each contributed to the e-cigarette work (Appendix C) in their own unique way. Thank you to Dr. Haihong Jiang and Dr. Yan Xie for giving me technical support and teaching me many different laboratory techniques. But more importantly, thank you for being good friends and for putting up with my bad Chinese. 谢谢. Thank you to Dr. Charles Bockman, Philosopher-in-Chief of the Creighton Pharmacology Department, for expanding my mind over hours of lively discussion. Discussions with you in Dr. Abel’s office are where I learned what it means to be a real pharmacologist. Thank you to Dr. Yaping Tu and Dr. Myron Toews, my committee members. Dr. Tu is a strong motivating force in our lab group and has a contagious passion for science. Dr. Toews taught me more about grammar than I ever learned in undergrad, was supportive of my career goals outside of academia, and heavily edited this dissertation so that it does not suck. v A huge thank you to Dr. Peter W. Abel for your unwavering support of my project, even when it started being all about computer modeling. Without your training and guidance none of this would have been possible. You always listened to me tirelessly ramble on and reminded me that “the only things you can do are the things that make sense.” Finally, thank you to the Department of Pharmacology, my fellow graduate students in the School of Medicine, and to Creighton University, my home for nine (!!) years. Go Jays! vi TABLE OF CONTENTS CHAPTER 1: ASTHMA ................................................................................................. 1 Introduction ................................................................................................................. 1 Epidemiology............................................................................................................... 1 Pathology ..................................................................................................................... 1 Drugs Used to Treat Asthma ....................................................................................... 3 β2 Adrenergic Receptor Agonists ........................................................................... 3 Theophylline ........................................................................................................... 4 Corticosteroids ........................................................................................................ 5 Leukotriene Receptor Antagonists .......................................................................... 5 Antibodies ............................................................................................................... 6 Antimuscarinics ...................................................................................................... 6 Lung Innervation ......................................................................................................... 7 Parasympathetic Nerves .......................................................................................... 8 Sympathetic Nerves .............................................................................................. 10 Sensory Nerves ..................................................................................................... 10 The Nervous System and Asthma ............................................................................. 11 Airways, Nerves, and Inflammation .......................................................................... 14 Objectives .................................................................................................................. 15 CHAPTER 2: DEVELOPMENT OF A COMPUTATIONAL MODEL TO SIMULATE NERVE-MEDIATED CONSTRICTION OF MOUSE TRACHEA ....... 18 Introduction ............................................................................................................... 18 Methods ..................................................................................................................... 21 Tissue Preparation and Electric Field Stimulation................................................ 21 First-Order Model ................................................................................................. 22 Inhibition Model ................................................................................................... 23 Method of Least Sum of Squares .......................................................................... 24 Capsaicin and Indomethacin Treatment ................................................................ 25 Data Analysis and Statistics .................................................................................. 25 Results ........................................................................................................................... 26 Control Trachea EFS Constriction ........................................................................ 26 Control Tissue First-Order Model Fits ................................................................. 28 Control Tissue Inhibition Model Fits .................................................................... 29 vii Tissue Treatment to Isolate ACh Constriction...................................................... 34 Treated Tissue First-Order Model Fits ................................................................. 34 Treated Tissue Inhibition Model Fits .................................................................... 36 Discussion ..................................................................................................................... 40 CHAPTER 3: DISTRIBUTIONAL DIFFERENCES IN FUNCTIONAL NEUROTRANSMITTER RELEASE IN MOUSE AIRWAYS ................................... 44 Introduction ............................................................................................................... 44 Methods ..................................................................................................................... 44 Electric Field Stimulation ..................................................................................... 45 Drug Treatments ..................................................................................................
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