Flavor-Dependent Effects of E-cigarette Liquids and their Chemical Constituents on Lung Epithelial Toxicity and Cell Ca2+ Signaling Public Deposited

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  • March 21, 2019
Creator
  • Rowell, Temperance
    • Affiliation: School of Medicine, Department of Cell Biology and Physiology
Abstract
  • E-cigarettes (e-cigs) are a cigarette alternative that do not contain tobacco or tar, and whose e-liquids are available in over 7,000 flavors. While marketed as a safer smoking alternative, the basic health effects of vaping commercially available e-liquids and their constituent components (i.e., propylene glycol (PG), vegetable glycerin (VG), nicotine, flavors) are not well understood. However, inhalation of diacetyl (butter flavor) has been shown to cause bronchiolitis obliterans (‘Popcorn Lung’). In this dissertation, we sought to better understand the biological effects of flavored e-liquids and their chemical constituents on airway cells. We first screened 13 flavored e-liquids, PG/VG, and nicotine for toxicity in a pulmonary epithelial cell line. We demonstrated that the responses were both dose- and flavor-dependent by exposing cells to either the unheated or heated (aerosolized) e-liquids. 4 of 13 flavored e-liquids had more pronounced toxicity effects than the PG/VG base or other flavors, and did not share a flavoring chemical between them that might be universally toxic. We then demonstrated that the toxic effects that we were measuring were either due to (1) direct cytotoxicity or (2) inhibiting cell proliferation. We further explored the ability of flavored e-liquids to inhibit cell proliferation by characterizing their effects on intracellular Ca2+ signaling, which can affect cell proliferation and apoptosis. Specifically, we demonstrated that a Banana Pudding-flavored e-liquid could stimulate phospholipase C-dependent inositol 1,4,5-triphosphate generation leading to ER Ca2+ depletion and elevations in cytosolic Ca2+. Moreover, we screened 100 additional e-liquids and found 42 of 100 elicited cytosolic Ca2+ responses, suggesting many flavors can alter Ca2+ homeostasis. Analysis of their chemical constituents correlated the presence of common flavorings (e.g., ethyl vanillin, vanillin, and ethyl maltol) with the cytosolic Ca2+ responses. Additional testing confirmed that those flavors caused dose-dependent Ca2+ signaling. Altered Ca2+ homeostasis can have profound effects on airway physiology and has been implicated in disease (i.e., cancer, autoimmune diseases, inflammation). Therefore, these products should be further assessed for their flavor-dependent effects on airway physiology (e.g., Ca2+ homeostasis) and potential consequences of long-term inhalation toxicity from chronic vaping.
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DOI
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Advisor
  • Burridge, Keith
  • Kesimer, Mehmet
  • Caron, Kathleen
  • Tarran, Robert
  • Jaspers, Ilona
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill
Graduation year
  • 2018
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