Public Health Consequences of E-Cigarettes (2018) / Chapter Skim
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7 Modes of Action
7 Modes of Action
Pages 223-254
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From page 223... ...
Since then, there has been a steady increase in the number of publications, with a cumulative total of 124 as of September 2017. This section discusses two modes of action -- endothelial cell dysfunction and oxidative stress -- that are associated with the development of a range of health outcomes.
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The two emerging questions are whether such effects are seen with e-cigarette use and what the magnitude of these effects is compared with traditional combustible tobacco cigarette smoke or to neither e-cigarette nor combustible tobacco use. It is well accepted that endothelial cell dysfunction produced by traditional tobacco burning involves various key initiating events, including a reduction in nitric oxide (NO)
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FIGURE 7-2 Endothelial cell dysfunction by tobacco smoke. SOURCE: Morris et al., 2015.
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The authors concluded that the effect of e-cigarette use on EPCs is similar in magnitude to that produced by combustible tobacco cigarette smoking, and is indicative of vascular injury. They attributed the unaffected MV values to insufficient exposure time because cotinine levels were much lower in their e-cigarette subjects compared with combustible tobacco cigarette users (Antoniewicz et al., 2016)
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As previously demonstrated with combustible tobacco cigarette smoke extracts, exposure of HUVECs to e-cigarette aerosols produces prominent changes in cell morphology and alters the functional endothelial monolayer. The authors clearly demonstrated that the source of the e-liquid and type of device used are determining factors in the cytotoxic potency of e-cigarette aerosols and the capacity to change endothelial cell morphology.
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HUVECs were exposed to extracts from combustible tobacco cigarettes and e-cigarettes. In some experiments, pure nicotine was used at a concentration that approximates the blood concentration of someone who smokes one combustible tobacco cigarette.
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The scratch wound assay using HUVECs was employed to measure rates of endothelial cell migration upon in vitro exposure to aqueous aerosol extracts from all test products. The results showed that wound repair after exposure to aqueous extract from the hybrid tobacco product and the commercial tobacco heating product was not significantly impaired, in contrast with the 3R4F reference combustible tobacco cigarette extract, which significantly impaired wound repair.
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The overall goal of this study was to evaluate the differences between combustible tobacco cigarette and e-cigarette smoking in oxidative stress and endothelial dysfunction. For this purpose, ultrasound assessment of basal brachial diameter and endothelial-dependent FMD of the brachial artery were investigated according to established guidelines.
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In another in vitro study, Teasdale and colleagues (2016) investigated the capacity of combustible tobacco cigarette smoke and electronic cigarette aerosol extracts to induce a stress response in endothelial cells.
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Interestingly, IL8 expression was reduced and NTPX1 was increased by nicotine. Based on the responsiveness of human coronary artery endothelial cells, the authors concluded that the use of e-cigarettes as a substitute for combustible tobacco cigarettes is likely to reduce harm to the cardiovascular system (Teasdale et al., 2016)
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conducted two studies examining effects of e-cigarettes on endothelial cells. The earlier study showed that in addition to damaging the pulmonary epithelium, soluble components of combustible tobacco cigarette smoke can directly damage lung endothelial cells by disrupting endothelial barrier function (Schweitzer et al., 2011)
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Overall, the in vitro studies showed that the endothelial barrier–disruptive effect of e-cigarette solutions is nicotine dose dependent and of a comparable magnitude to that produced by 3 percent combustible tobacco cigarette smoke extract exposure (a concentration known not to cause cell death)
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Figure 7-3, obtained from Schweitzer and colleagues (2015) , depicts the proposed signaling cascade triggered by nicotine that partially overlaps with that used by combustible tobacco cigarette smoke extracts to disrupt the endothelial cell barriers and cell proliferation.
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In a more recent publication, Taylor and colleagues (2016) compared the effects of e-cigarette aqueous extracts generated from two commercial products to e-cigarette aqueous extracts from the 3R4F reference combustible tobacco cigarette on human bronchial epithelial cell (HBEC)
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, evaluation of oxidative stress with e-cigarette use is essential to identify and understand the potential biological and toxicological consequences of any pro-oxidant state produced by chemicals present and/or generated during e-cigarette use. The emerging in vitro literature investigating oxidative stress from e-cigarette use employs either immortalized cell lines, tumor cell lines, or primary cells in culture.
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In addition, selected in vivo studies assessing the capacity of e-cigarettes to produce oxidative stress also will be discussed in support of and/or complimentary to in vitro studies.
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The time of exposure to both combustible tobacco cigarette smoke and e-cigarette aerosols ranged from 8 to 288 minutes. Effects on BEAS-2B cells analyzed were cytotoxicity, oxidative stress, and inflammatory response.
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Although the respiratory and cardiovascular systems are major targets in tobacco-related pathologies, cigarette smoking apparently accelerates the progression of chronic kidney disease, with nicotine being a proven exacerbator of ischemia-mediated renal injury via oxidative stress. Although the in vitro cytotoxicity of e-liquids has been investigated in various cardiovascular-derived cell lines, the effects of e-cigarettes in the renal system are unknown.
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The outcome of the in vitro studies was also similar. Cytotoxicity and cell morphology changes were evident in A549 cells exposed to combustible tobacco cigarette smoke, but not to the e-cigarette extract.
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. From these s tudies, the authors suggested that the blood–brain barrier dysfunction and increased risk for stroke from combustible tobacco smoke resembles the cerebrovascular diseases seen in pathogenic stages of type 2 diabetes that also involve some of the same mediators, such as oxidative stress,
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Interestingly, the in vivo studies show that metformin treatment confers partial support against the detrimental effects of both combustible tobacco cigarette smoke and e-cigarettes in stroke injury by reducing oxidative stress and inflammation (Kaisar et al., 2017)
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Gene ontology was also performed to identify gene expression patterns with roles in specific biological processes or signaling pathways highly enriched within the different clusters. Among the genes upregulated by e-cigarette aerosol and combustible tobacco cigarette smoke, they found enrichment for genes involved in oxidative stress, apoptosis, and DNA damage.
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The authors justify the importance of this new genomics analysis with e-cigarette exposure based on their past evidence documenting alterations in airway epithelial gene expression patterns by combustible tobacco cigarette smoke that can serve as a biomarker of pulmonary diseases in smokers, including the early detection of cancer (Beane et al., 2007; Silvestri et al., 2015)
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To also analyze oxidative stress, samples from all the different cell types exposed to e-liquid aerosols, combustible tobacco cigarette smoke, and clear air were analyzed using the ROS-Glo™ H2O2 fluorescence-based assay. The results were in complete agreement with the cell viability data.
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Not only does this study document the use of a new immortalized HBEC cell line for in vitro toxicity testing of -cigarettes, but it also adds e further evidence that e-cigarette aerosols are cytotoxic and produce oxidative stress at levels that are significantly lower than those produced by combustible tobacco cigarette smoke (Scheffler et al., 2015)
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SOURCE: Taylor et al., 2016. tested in the NCI-H292 human bronchial epithelial cells do not contain either the chemical drivers or the sufficient concentrations to produce oxidative stress or cytotoxicity.
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However, in the absence of comparative experiments that include expo sure to cigarette smoke, the magnitude and physiological relevance of the effects observed with e-cigarette relative to combustible tobacco cigarette smoke remain uncertain.
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Although this supports the biological plausibility of tissue injury and disease from long-term exposure to e-cigarette aerosols, generation of reactive oxygen species and oxidative stress induction are generally lower from e-cigarettes than from combustible tobacco cigarette smoke. Adverse outcome pathway (AOP)
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electronic cigarette smoking on oxidative stress and vascular function. Chest 150(3)
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2011. Mechanisms of lung endothelial barrier disruption induced by cigarette smoke: Role of oxidative stress and ceramides.
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2016. E-cigarette aerosols induce lower oxidative stress in vitro when compared to tobacco smoke.
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