DOI
https://doi.org/10.25772/4TPQ-NN81
Defense Date
2023
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Integrative Life Sciences
First Advisor
John Ryan
Abstract
Asthma affects over 300 million people worldwide, and its prevalence is increasing. Asthma can be characterized by bronchoconstriction, pulmonary inflammation, and airway remodeling. Mast cells are a key player in allergic asthma and can be activated by a variety of different stimuli, such as IgE-crosslinking and IL-33. Though there are current immunotherapies available to alleviate these symptoms, they can have unwanted side effects. Thus, searching for new treatment options is an attractive topic. Interestingly, there is a sexual dimorphism present in the asthmatic population. In children, there is a higher prevalence of asthma in boys compared to girls. However, after puberty, women are almost twice as likely to have asthma than men. Our studies show that IL-33 activated female mast cells secrete elevated levels of IL-6 compared to male cells, suggesting a sex-dependent variation that could contribute to asthma. These trends were also seen in vivo, as WT females have greater IL-33-induced neutrophil and eosinophil influx than WT males. When searching for a mechanism to explain this disparity, we found that IL-33 induces ATP release from mast cells. Intriguingly, we found that mast cells cultured from mice lacking the ATP receptor P2X3 showed no sex differences when stimulated with IL-33, suggesting that P2X3 plays a role in maintaining sexual dimorphism. Interestingly, when utilizing a P2X3 inhibitor, BLU-5937, we found that it can suppress IL-33-mediated inflammation in vivo in female but not male mice. BLU-5937 is clinically relevant because it is currently in Phase II clinical trials for suppressing chronic cough and has already demonstrated its safety in humans. These data are novel because they suggest one mechanism by which asthma is worse in females, and provide P2X3 as a new therapeutic target to suppress mast cell function.
Rights
© Sydney Ann Kee
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
12-15-2023