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Review
. 2023 Oct 31;12(21):2552.
doi: 10.3390/cells12212552.

Mechanisms of E-Cigarette Vape-Induced Epithelial Cell Damage

Emily Auschwitz  1 , Jasmine Almeda  1 , Claudia D Andl  1
Affiliations
Review

Mechanisms of E-Cigarette Vape-Induced Epithelial Cell Damage

Emily Auschwitz et al. Cells. .

Abstract

E-cigarette use has been reported to affect cell viability, induce DNA damage, and modulate an inflammatory response resulting in negative health consequences. Most studies focus on oral and lung disease associated with e-cigarette use. However, tissue damage can be found in the cardio-vascular system and even the bladder. While the levels of carcinogenic compounds found in e-cigarette aerosols are lower than those in conventional cigarette smoke, the toxicants generated by the heat of the vaping device may include probable human carcinogens. Furthermore, nicotine, although not a carcinogen, can be metabolized to nitrosamines. Nitrosamines are known carcinogens and have been shown to be present in the saliva of e-cig users, demonstrating the health risk of e-cigarette vaping. E-cig vape can induce DNA adducts, promoting oxidative stress and DNA damage and NF-kB-driven inflammation. Together, these processes increase the transcription of pro-inflammatory cytokines. This creates a microenvironment thought to play a key role in tumorigenesis, although it is too early to know the long-term effects of vaping. This review considers different aspects of e-cigarette-induced cellular changes, including the generation of reactive oxygen species, DNA damage, DNA repair, inflammation, and the possible tumorigenic effects.

Keywords: DNA damage; cancer; cell signaling; e-cigarette vape; inflammation; reactive oxygen species.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Pathways of inflammatory signaling. E-cig aerosols induce the expression of pattern-recognition receptors such as TLR and the secretion of pro-inflammatory cytokines such as IL1B and TNFα and their respective receptors, particularly in response to menthol-flavored e-cigs. In the oral cavity (left part of the figure), e-cig vape affects the healthy oral microbiota by inhibiting commensals and favoring growth and biofilm formation of cariogenic bacteria, especially in the presence of sweet flavors containing sugar. IL4 suppression further supports colonization with pathogenic bacteria. In human airway epithelial cells (right part of the figure), e-cig aerosols also increase inflammatory cytokines, such as IL6 and IL8, secreted by macrophages in response to, for example, cinnamon- and caramel-flavored e-vape containing ethyl maltol. Acrolein, found in e-cig vape, inhibits the Fc receptor and function of neutrophils. Additionally, exposure to even a 100% propylene glycol e-cig liquid without flavors and nicotine results in increased mucus concentration, trapping bacteria and viruses and leading to IL8-mediated inflammation relevant to lung disease and COPD.
Figure 2
Figure 2
The regulation of reactive oxygen species. Under normal conditions, glutathione functions in scavenging reactive oxygen species, and levels of NRF2 remain low due to ubiquitin-mediated degradation in the proteasome (left panel). If oxidative stress increases, NRF2 escapes protein degradation upon phosphorylation and separation from KEAP1, and it enters the nucleus to regulate gene expression by binding the antioxidant response element (ARE) as a normal reaction in response to oxidative stress. Flavoring, acrolein, and aldehydes can interfere with the normal oxidative stress response: Acrolein can induce the expression of KEAP1, and aldehydes induce NOX proteins, which can result in high levels of ROS. Copper nanoparticles in e-cig aerosols increase mitochondrial dysfunction, as a consequence of mtROS associated with an electron leak. In the presence of e-cigs, glutathione levels are diminished and ROS created by e-cig exposure, including unvaporized e-liquids and flavorings, cannot be scavenged.
Figure 3
Figure 3
Types of e-cig-induced DNA damage. The dominant pathway of nicotine metabolism in humans is the formation of cotinine, the first step of which is catalyzed by cytochrome P450 (CYP P450). Nicotine can be metabolized to 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N’-nitrosonornicotine (NNN). Both of these compounds, as well as acrolein (y-OH-Acr-dGUO), can lead to DNA adduct formation. E-cig aerosol-induced reactive oxygen species (ROS) can also induce DNA oxidation, such as 8-oxo-dG. Usually detected by XPC and repaired via excision by OGG1, aldehydes in the e-cig vape inhibit this repair step causing potential mutations. Nicotine and nicotine-free vape induce DNA fragmentation, including DNA single (SS)- and double-strand breaks (DSB), which require DNA damage repair proteins such as pH2AX to be recruited. Transversions (base-pair substitutions) lead to mutations, e.g., in genes such as Ras and p53. Aldehydes suppress DNA damage repair as they inhibit cytochrome (CYP)-mediated detoxification. Overall, levels of DNA damage correlate with the amount of vape consumed as well as additives such as flavoring, especially sweet, fruit, and menthol flavors.
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