ORCID
0000-0002-3734-9615
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
Asthma is a chronic respiratory condition characterized by airflow obstruction and breathing difficulties brought about by factors including airway inflammation and pulmonary remodeling that affect the smooth muscle cells of the airway and oftentimes diagnosed using tools to assess hyperresponsiveness to bronchoconstrictive agonists that trigger the smooth muscle. In allergic asthma, immune responses involving cytokines such as IL-4, IL-5, and IL-13, along with leukocytes including eosinophils and type 2 T-helper cells, drive inflammation and structural changes, including fibrosis and airway thickening. Bronchial smooth muscle (BSM) plays a critical role in asthma pathophysiology by exacerbating airway narrowing through pro-inflammatory cytokine release and increased contractility in response to allergens, microbial products, or inflammatory mediators. While bronchodilators, corticosteroids, and biologics effectively manage asthma for many patients, alternative or complementary therapies are needed for difficult-to-treat cases, particularly in obese and allergic individuals.Previous research has highlighted the potential for metabolic interventions to modify airway physiology. Obesity-associated asthma, which often presents with heightened airway hyperresponsiveness, is linked to metabolic dysfunction, and weight loss has been shown to improve symptoms and reduce inflammation. Emerging studies suggest that therapeutic ketosis, achieved through dietary interventions or exogenous ketone supplementation, may modulate airway function by altering inflammatory and contractile responses in bronchial smooth muscle. The primary ketone body, β-hydroxybutyrate (BHB), augmented during times of ketosis, has demonstrated beneficial properties across various cell types and disease models. However, its specific effects on bronchial smooth muscle and airway hyperresponsiveness remain incompletely understood. We examined the effects of BHB on human bronchial smooth muscle cells (HBSMC) in vitro and mouse precision-cut lung slices (PCLS) ex vivo. In a dose-dependent manner, BHB reduced house dust mite extract (HDM)-induced morphological changes in BSM cells and decreased HDM protease activity. Additionally, BHB suppressed IL-1β-induced pro-inflammatory cytokine production and inhibited histamine-induced contraction and bronchoconstriction, as observed through brightfield microscopy of HBSMC and light microscopy of PCLS, respectively. These findings suggest that BHB mitigates airway narrowing by reducing smooth muscle contraction and inflammatory signaling. Further analyses indicate that these effects may be mediated, at least in part, through the activation of Free Fatty Acid Receptor 3 (FFAR3), a proposed mechanism by which BHB elicits its protective effects on bronchial smooth muscle. These results highlight bronchial smooth muscle as a key target of therapeutic ketosis and support the potential of BHB as a novel adjunct therapy for asthma, particularly in individuals with difficult-to-treat disease.
Language
en
Number of Pages
205 p.
Recommended Citation
Fastiggi, Vivia Amanda, "Therapeutic Ketosis Attenuates Asthma Associated Airway Hyperreponsiveness By Targeting Bronchial Smooth Muscle" (2025). Graduate College Dissertations and Theses. 2053.
https://scholarworks.uvm.edu/graddis/2053