Year of Award

2015

Document Type

Dissertation

Degree Type

Doctor of Philosophy (PhD)

Degree Name

Toxicology

Department or School/College

Department of Biomedical and Pharmaceutical Sciences

Committee Chair

Kevan Roberts

Commitee Members

Andrij Holian, Tony Ward, Scott Wetzel, Mike Minnick

Keywords

Asthma, GSNOR, IgA, Mucosal, Natural Killer cells, Prostacyclin

Publisher

The University of Montana

Abstract

Despite massive efforts to develop effective therapeutic options for the treatment of asthma, disease prevalence continues to increase. Approximately 300 million people worldwide have been estimated to be affected by asthma, and it remains a leading cause of childhood hospitalization. While environmental as well as genetic causative agents have been identified, the heterogeneous nature of the disease has proven difficult to effectively treat. Asthma is characterized as chronic inflammation of the airway characterized by increased airway hyperreactivity, increased goblet cell hyperplasia, and airway remodeling. While these effects are traditionally regarded to be mediated through the actions of CD4+ Th2 cells, recent advances have suggested that underlying innate immune cell populations within the airway mucosa might exert a critical role in the development of asthma. However, the inflammatory mediators and respective mechanisms responsible for this role remain poorly understood. In this study, we attempt to elucidate the role of two mucosal-associated inflammatory mediators, S-nitrosoglutathione and prostaglandin I2 in the pathogenesis of asthma in two distinct mouse models of allergic asthma. In our first study, we demonstrated that therapeutic treatment using SPL-334, a specific inhibitor of S-nitrosoglutathione reductase, significantly reduced the development of allergic airway inflammation. In our second study, we demonstrated that loss of prostaglandin I2 signaling resulted in significant alterations in pulmonary NK cells. Using an in vivo depletion method, we demonstrated that pulmonary NK cells are responsible for attenuated development of house dust-mite induced allergic airway inflammation. In our third and final study, we demonstrated that loss of prostaglandin I2 signaling leads to substantial reduction in the production of non-antigen-specific IgG2b and IgA via an undetermined mechanism. The results of this dissertation strongly suggest that regulation of mucosal immunity by inflammatory mediators such as S-nitrosoglutathione and prostaglandin I2 can have profound effects on the development of mucosal-associated diseases, and offer novel insights into potential future therapeutic targets for the treatment of diseases such as asthma.

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© Copyright 2015 Bryan Joseph Simons