Regulation of airway reactivity: interactions between neuronal and immune pathways in the lung Public Deposited

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  • March 21, 2019
Creator
  • Cyphert, Jaime Marie
    • Affiliation: School of Medicine, Curriculum in Genetics and Molecular Biology
Abstract
  • The prevalence of asthma has been on the rise since the 1970s, affecting more than 300 million people worldwide. In recent years, approximately 250,000 deaths per year have been attributed to the condition. The majority of these deaths are likely a direct result of airway obstruction, of which constriction of airway smooth muscle plays a significant role. Although several bronchodilators are currently on the market for alleviation of airway constriction, not all patients are responsive to these treatments. This underlies the importance of understanding the mechanisms triggering smooth muscle constriction so that additional drug targets can be discovered to help prevent or reverse airway constriction during asthmatic exacerbations. In this dissertation I utilize two approaches to analyze immune-related airway constriction in the mouse in an attempt to further understand the mechanism behind the human condition. The majority of asthmatics also have allergies, which can trigger both enhanced inflammation of the airways and airway constriction. Therefore, the first approach involved modeling allergic airway constriction in both the naive and inflamed mouse lung to examine the mechanisms of IgE-mediated bronchoconstriction. Genetic, pharmacological, and surgical methods were then used to explore the cell types, mediators, and receptors involved in this response. The second approach involved the triggering of airway constriction through a non-allergic mechanism. In these studies, the thromboxane analog U46619 was used to elicit dose-dependent airway constriction. As the thromboxane receptor, Tp, is expressed on multiple cell types, mice carrying a tissue-specific deletion of this receptor were examined to define the cell types involved in U46619-mediated bronchoconstriction in both the naive and inflamed lung. Asthma is a highly complex disease involving the combined effects of both genetic and environmental effects and therefore it is unlikely to be able to model the disease itself accurately in a laboratory animal that does not spontaneously develop the condition. However, it is possible to closely approximate several pathophysiological symptoms of asthma in the mouse, and using these models, the many mechanisms underlying the conditions of asthma can be teased away from the complexity of the condition as a whole.
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  • In Copyright
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  • "... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Curriculum of Genetics and Molecular Biology."
Advisor
  • Koller, Beverly H.
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  • Chapel Hill, NC
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  • Open access
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