MODIFICATION OF RESPIRATORY SYSTEM INNATE DEFENSE MECHANISMS BY FLAVORING AGENTS IN ELECTRONIC CIGARETTES Public Deposited

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  • March 20, 2019
Creator
  • Clapp, Phillip
    • Affiliation: School of Medicine, Curriculum in Toxicology
Abstract
  • Electronic cigarettes (e-cigarettes) have emerged as a potentially safer alternative to traditional cigarettes. Because e-cigarettes deliver nicotine without burning tobacco, their use likely confers a lower overall health risk than inhaling combustible tobacco products. However, e-cigarette emissions contain solvents (propylene glycol and glycerol), flavorings, and other additives, which have not been evaluated for inhalation toxicities. The inhalation of flavoring agents, which are frequently aldehydes, poses a significant unknown in regards to the potential health risks of e-cigarette use as many of these chemicals are structurally similar to toxic aldehydes in cigarette smoke. Furthermore, aldehyde flavoring agents are often used at exceedingly high concentrations in e-cigarettes which may lead to high exposure doses. The work presented in this dissertation focuses on evaluating the effects of flavored e-cigarettes, particularly those containing ⍺,β-unsaturated cinnamaldehyde, on respiratory innate defense mechanisms and assessing whether and how these flavorings may alter susceptibility to respiratory infections. In Chapter 2, we report that cinnamon-flavored e-cigarette refill liquids and cinnamaldehyde modify human respiratory innate immune cell defense functions, including neutrophil and alveolar macrophage phagocytosis, neutrophil extracellular trap formation, and natural killer (NK) cell-mediated killing of leukemia cells. Based on these observations we established the cinnamaldehyde exposure concentrations that inhibit normal defense functions (IC50) and induce cytotoxicity (LC50). In Chapter 3, we report that cinnamon-flavored e-liquids, cinnamon e-cigarette aerosols, and cinnamaldehyde temporarily suppress motile cilia on human bronchial epithelial cells (hBE) and that this response is driven by transient inhibition of mitochondrial respiration and glycolysis. In Chapter 4, we report that cinnamaldehyde, guaiacol, and eugenol elicit a dose-dependent bimodal effect on Nrf2-pathway activation in bronchial epithelial cells (Beas-2B) and cinnamaldehyde exposure significantly depletes cellular glutathione (GSH) levels at low micromolar concentrations. Taken together, the work presented in this dissertation demonstrates that flavoring agents, in the context of e-cigarette use, are capable of dysregulating essential respiratory defense responses, which may increase susceptibility of respiratory infections and lung disease in e-cigarette users. It is our hope that the information provided here will be useful in the development of health-protective policies aimed at reducing or eliminating harmful and potentially harmful chemicals from e-cigarettes.
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Advisor
  • Hazari, Mehdi
  • Jaspers, Ilona
  • Bennett, William
  • Weissman, Bernard
  • Koller, Beverly H.
  • Noah, Terry
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2018
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