ORCID
https://orcid.org/0009-0009-9825-4116
Date of Award
2025
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Cellular, Molecular and Biomedical Sciences
First Advisor
Matthew E. Poynter
Abstract
Obesity is an increasingly prevalent health crisis affecting the outcome of airway diseases including asthma. Obese asthmatics have poorly controlled symptoms despite receiving increased dosages of standard asthma treatments. The most effective means of improving asthma symptoms in obese patients is through weight loss, which leads to a reduction in adipose tissue mass and the liberation of free fatty acids. These free fatty acids are converted into ketone bodies, high-energy, secondary metabolites formed when fat is utilized to meet energetic demands. Beta-hydroxybutyrate (BHB), one of the major ketone bodies produced, has potential as a therapeutic intervention. Previous studies have demonstrated that therapeutic ketosis through ketogenic diets or supplementation with ketone precursors decreases airway hyperreactivity in mouse models of both allergic and obese asthma.
The airway epithelium is the physical barrier that protects the lungs from the external environment and is a critical component of initial host defense against inhaled molecules and pathogens. Airway epithelial cells can detect pathogens, react to irritants and allergens, and respond to injury by initiating and orchestrating inflammatory responses. Given their central role in the lung, it is no surprise that these cells are major contributors to the pathophysiology of asthma, in which there is reduced barrier integrity, mucus hypersecretion, and augmented secretion of cytokines that sustain chronic inflammation. The effect of weight loss and therapeutic ketosis on airway epithelial responses remained unexplored.
We examined the effects of weight loss on airway epithelial cells using samples from obese patients undergoing bariatric surgery, including non-allergic and allergic obese asthmatics. Post-surgery plasma induced lower pro-inflammatory responses than pre-surgery plasma, and BHB was transiently increased in circulation prior to major weight loss. We also investigated BHB’s effects on airway epithelial processes including pro-inflammatory and anti-viral responses, and mucus secretion. BHB attenuated house dust mite (HDM)-induced morphological changes and IL-8 secretion, partly by inhibiting HDM protease activity. While BHB modulated responses to viral double-stranded RNA (dsRNA) mimetics, it had no effect on influenza infection in vitro. BHB did not alter constitutive or inducible mucus secretion.
These findings suggest that therapeutic ketosis directly modulates select airway epithelial responses, most notably pro-inflammatory cytokine responses from a protease allergen and viral dsRNA mimetics, and further support the utilization of BHB as a complement to existing therapies for the treatment of obese asthma.
Language
en
Number of Pages
197 p.
Recommended Citation
Peña García, Paola E., "Weight Loss and Therapeutic Ketosis Improve Obese Asthma by Modulating Airway Epithelial Pro-Inflammatory Responses" (2025). Graduate College Dissertations and Theses. 2114.
https://scholarworks.uvm.edu/graddis/2114