The paradox of the safer cigarette: understanding the pulmonary effects of electronic cigarettes

Kassandra Allbright, John Villandre, Laura E. Crotty Alexander, Michael Zhang, Kambez H. Benam, John Evankovich, Melanie Königshoff, Divay Chandra
European Respiratory Journal 2024 63: 2301494; DOI: 10.1183/13993003.01494-2023

Abstract

Electronic cigarette (e-cigarette) use continues to rise globally. E-cigarettes have been presented as safer alternatives to combustion cigarettes that can mitigate the harm associated with tobacco products; however, the degree to which e-cigarette use itself can lead to morbidity and mortality is not fully defined. Herein we describe how e-cigarettes function; discuss the current knowledge of the effects of e-cigarette aerosol on lung cell cytotoxicity, inflammation, antipathogen immune response, mucociliary clearance, oxidative stress, DNA damage, carcinogenesis, matrix remodelling and airway hyperresponsiveness; and summarise the impact on lung diseases, including COPD, respiratory infection, lung cancer and asthma. We highlight how the inclusion of nicotine or flavouring compounds in e-liquids can impact lung toxicity. Finally, we consider the paradox of the safer cigarette: the toxicities of e-cigarettes that can mitigate their potential to serve as a harm reduction tool in the fight against traditional cigarettes, and we summarise the research needed in this underinvestigated area.

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Introduction

In 1560 the French diplomat Jean Nicot de Villemain presented tobacco to the French king as a means of harm reduction, as it was believed it could protect the populace from diseases such as the plague. Soon, tobacco was in widespread use in France, Europe and the rest of the world, which imposed an enormous burden of morbidity and mortality, which we continue to contend with to this day.

Today, electronic cigarettes (e-cigarettes) are being presented as a means of harm reduction that will protect the populace from the harms of tobacco products [1]. Unlike the 1600s, we are now in the era of evidence-based medicine and can use scientific data to cross-examine the potential for harm reduction, hopefully before e-cigarette use becomes entrenched in the community.

Accordingly, the purpose of this review is threefold: 1) to explain how e-cigarettes function; 2) to summarise the scientific evidence to date on the effect of e-cigarettes on lung health; and 3) to understand how e-cigarettes may impact tobacco-related lung disease morbidity and mortality. Our overall objective is not to pass judgement on controversial health policies that promote or restrict e-cigarette use, but to summarise and place into context the rapidly evolving scientific evidence so readers can draw their own conclusions.

How e-cigarettes function

Physicians and researchers need to understand how e-cigarettes function, in order to interact meaningfully with patients who use these devices and to appreciate how heterogeneous these devices are and how this heterogeneity can impact the potential for toxicity.

The components of an e-cigarette

E-cigarettes have three essential components: a battery, an atomiser and a mouthpiece (figure 1). The e-cigarette is activated either by a flow sensor that detects negative pressure applied to the mouthpiece, or when the user presses a button on the device. Once activated, the battery provides an electric current to a metal coil inside the atomiser that heats the e-liquid. Applying suction at the mouthpiece pulls the heated e-liquid through the atomiser, resulting in an aerosol (commonly called vapour) which is inhaled by the user.

FIGURE 1
FIGURE 1

Components of a typical electronic cigarette.

Generations of e-cigarettes

Different classifications of e-cigarettes exist; here, we follow the description of four generations of devices put forth by the Centers for Disease Control and Prevention [2] (figure 2). First-generation devices, also called “cig-a-likes”, mimic the appearance of combustion cigarettes and are disposable. Second-generation devices or “vape pens” are reusable, with rechargeable batteries and refillable tanks. Third-generation devices have user-modifiable settings, such as the wattage, leading to the name “mods”. By changing the power settings, the user can modify the properties of the aerosol to their liking. Finally, fourth-generation devices incorporate a single-use “pod” that contains both the e-liquid and heating coil connected to a rechargeable or single-use battery called “pod” devices. Fully disposable devices (“use and throw”) also belong to the fourth generation. Many fourth-generation devices are compact and easy to conceal and have largely replaced first and second-generation devices among users.

FIGURE 2
FIGURE 2

Generations of electronic cigarettes as defined by the Centers for Disease Control and Prevention.

The composition of e-liquid

A detailed discussion of e-liquid chemistry is beyond the scope of this review [8]. However, healthcare professionals and researchers should understand the basic composition of e-liquids and methods of e-cigarette use, as these can impact lung toxicity. The main constituent of e-liquids is a solvent carrier, typically a mix of propylene glycol (PG) and glycerol (commonly called vegetable glycerin (VG)), which generates an aerosol that mimics combustion cigarette smoke when heated. Commonly used PG:VG ratios are 70:30, 50:50 and 30:70 [4]. Altering the PG:VG ratio changes the aerosol's “mouth-feel” and density [3]. E-cigarette users often complain of a dry mouth and throat that probably results from the humectant nature of PG and VG. Both substances are used extensively in pharmaceuticals, cosmetics and processed foods. The United States Food and Drug Administration places both chemicals in the “generally recognised as safe” category for gastrointestinal ingestion, but not for heating and inhalation into the lungs [5]. Thermal degradation of PG and VG inside an e-cigarette releases multifunctional carbonyls into the aerosol, including known toxins such as formaldehyde [6, 7]. The toxicity of these compounds when inhaled by humans long-term needs to be better understood. Nicotine is frequently present in e-liquids. Fourth-generation devices commonly use high concentrations of nicotine salts (59 mg·mL−1 or 5% by weight) instead of the low concentration of freebase nicotine used in prior generations (most commonly 3–6 mg·mL−1) [8]. Nicotine salts are better tolerated at higher concentrations than freebase nicotine, because the resulting aerosol is less bitter and drying to the throat [8]. In addition, nicotine salts are more efficiently absorbed into the bloodstream than freebase nicotine in clinical studies [9, 10]. This higher systemic absorption may have implications for toxicity [11]; for example, whole-body exposure to aerosol from e-liquid containing PG with nicotine (25 mg·mL−1) versus PG alone resulted in lung inflammation conditional on the presence of the α7 nicotinic acetylcholine receptor [12].

Manufacturers can add a wide variety of flavouring compounds to e-liquids; ∼15 000 per some estimates [4]. Information on the biological effects of flavouring compounds is gradually becoming available and is summarised in this review. E-liquids can also contain cannabinoids, alcohol and food-grade oils. Tetrahydrocannabinol (THC)-containing e-liquids are a distinct class of e-liquids, as they require solvents such as medium-chain glycerides from palm or coconut oil and/or polyethylene glycols to keep the THC in solution; these solvents have unique toxicities that are outside the scope of this review [13].

The heating coil and wick

E-cigarettes contain a metal coil commonly made of aluminium, chromium, iron or nickel alloys [8]. The coil can degrade with use, leading to aerosolisation and inhalation of these metals [21, 22]. The type of metal used in the coil can also impact lung toxicity by altering the chemistry of the aerosol. For example, aerosol generated by a coil made from nickel–chromium alloy induced acute respiratory distress that did not occur when the coil was replaced with one made of stainless steel [23]. Most coils contain a cotton wick, but ceramic, silica, stainless steel mesh and rayon wicks can also be used [8]. The wick absorbs the e-liquid and keeps it in contact with the coil. Silica particles have been detected in the aerosol from e-cigarettes containing silica wicks [26]. Finally, users can make modifications to the e-cigarette that are not intended by the manufacturer (called “hacking”), such as using homemade coils [32] or altering the voltage of the heating element [33, 34]. These modifications can alter the chemistry and, therefore, the pulmonary toxicity of the aerosol.

Scientific evidence on the effect of e-cigarettes on lung biology

Search strategy for literature review

We conducted a PubMed search using the search term (((“electronic nicotine delivery systems” [Medical Subject Headings (MeSH)] OR “vaping”[MeSH] OR “e-cigarette vapor”[MeSH]) OR vaping) OR e-cigarettes) OR electronic cigarettes, up to date at 1 January 2024. The search resulted in 18 333 articles that were manually examined for relevance to this review by three authors (K. Allbright, J. Villandre and D. Chandra). We excluded studies that 1) were funded by the tobacco industry or conducted by investigators with links to the tobacco industry; 2) focused on nonpulmonary effects of e-cigarette use; 3) assessed impact of maternal e-cigarette use on progeny health; 4) investigated e-cigarettes as a smoking cessation tool; 5) focused primarily on the coronavirus disease 2019 (COVID-19) pandemic (use of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as a model of viral infection was acceptable); or 6) focused solely on c-cigarette or vaping use-associated lung injury. The latter two were excluded as they are specialised subtopics related to e-cigarettes with extensive literature reviewed elsewhere [21–23].

Overview of literature summary

The summary of the scientific evidence on the effect of e-cigarettes on the lungs herein is split into seven categories representing an important pathological process, i.e. cytotoxicity; inflammation; antipathogen immune response; mucociliary clearance; oxidative stress, DNA damage and lung cancer; matrix remodelling; and airway hyperresponsiveness (figure 3). These categories were chosen because there were an adequate number of articles in each category to allow for an interpretive review and because these pathological processes underpin a variety of common lung diseases.

FIGURE 3
FIGURE 3

Summary of the potential toxicities of e-cigarette aerosol on the lungs. IL: interleukin; CXCL: chemokine (C-X-C motif) ligand; IFN: interferon; TNF: tumour necrosis factor; MIP: macrophage inflammatory protein; 8-oxo-dG: 8-oxo-2′-deoxyguanosine; H2O2: hydrogen peroxide; HO: haem oxygenase; GCLM: glutamate-cysteine ligase modifier; GCLC: glutamate-cysteine ligase catalytic subunit; GPX: glutathione peroxidase; MCP: monocyte chemoattractant protein; AT2: alveolar type 2 cell.

Impact of e-cigarettes on pulmonary cytotoxicity

Independent studies report that e-cigarette aerosol can be cytotoxic to pulmonary cells (figure 3). Specifically, e-cigarette aerosol has been found to be cytotoxic to airway epithelial and macrophage cell lines [24–27], as well as a variety of primary human cells such as alveolar type II cells [28], macrophages [29], small airway epithelial cells [30] and fibroblasts [31].

However, most studies find that the cytotoxicity of e-cigarette aerosol is less than that of combustion cigarette smoke [26, 32–34]. For example, cell death occurred in the lungs of mice exposed to combustion cigarette smoke for 3 days, but not in mice exposed to e-cigarette aerosol at the same dose [32]. Similarly, combustion cigarette smoke was more cytotoxic to primary airway epithelial cells cultured at air–liquid interface than e-cigarette aerosol at the same dose [33, 34].

The contribution of flavouring compounds towards the cytotoxicity of e-cigarette aerosol is an area of active research. Bahl et al. [35] found that “cinnamon ceylon” flavouring was the most cytotoxic among 36 flavourings tested in human pulmonary fibroblasts and embryonic stem cells. Bengalli et al. [36] found menthol to be the most cytotoxic flavouring in human epithelial monocultures and three-dimensional human epithelial/endothelial co-culture models. Similarly, menthol flavouring enhanced the cytotoxicity of e-cigarette extracts in mouse precision-cut lung slices [37].

In summary, chronic pulmonary cytotoxicity may occur with e-cigarette use. Cinnamon and menthol flavourings may potentiate these effects. Pulmonary cytotoxicity is known to potentiate various processes implicated in the pathogenesis of obstructive and fibrotic lung diseases such as COPD and idiopathic pulmonary fibrosis, such as dysregulated repair, senescence via exhaustion of stem cell replicative potential, and inflammation [38–42]. Therefore, chronic e-cigarette use may contribute to the development of obstructive and fibrotic lung diseases and may exacerbate pre-existing disease.

Impact of e-cigarettes on lung inflammation

E-cigarette aerosol has been consistently found to induce acute and chronic inflammation in vitro and in vivo (figure 3). Specifically, an acute increase in neutrophilic inflammation, neutrophil recruitment and expression of cytokines involved in innate immunity (interleukin (IL)-8, IL-1β and tumour necrosis factor (TNF)-α) occurred in the lungs of mice exposed to e-cigarette aerosols [24, 32, 43–47]. Similarly, acute exposure to e-cigarette aerosol increased secretion of IL-8 by primary human alveolar type 2 cells [28, 36], increased mRNA for IL-6, TNF-α, chemokine (C-X-C motif) ligand (CXCL)-8, monocyte chemoattractant protein-1 by primary human alveolar macrophages [29], increased release of endothelial microparticles in humans [48], increased IL-8 and IL-12A expression by human bronchial organoids and A549 cells [49] and increased production of IL-6 and IL-8 by primary human fibroblasts [31], primary human tracheobronchial epithelial cells [50, 51] and human monocyte-derived dendritic cells [52]. Chronic exposure of mice to e-cigarette aerosol (>1 month) increased pro-inflammatory cytokines in the circulation [53], lung parenchyma [54] and airways [55], and neutrophils and lymphocytes in bronchoalveolar lavage fluid [55, 56]. In contrast, two studies found that e-cigarette aerosol does not increase inflammatory responses in the lungs of mice [57, 58]. These differences may be a dosing effect, as suggested by a study where one puff per minute exposure for 20 min did not induce neutrophilic infiltration in the lungs of mice, while four puffs per minute for the same duration did [43]. Another explanation would be the different chemical composition of each e-cigarette, leading to differing toxic and inflammatory impact on lung tissue [59, 60].

Multiple studies report that e-cigarette aerosol induces less inflammation than combustion cigarette smoke [32, 57, 61]. For example, e-cigarette aerosol exposure for 3 days increased only IL-1β mRNA levels in the lungs of mice, while exposure to combustion cigarette smoke for the same duration also increased IL-6 and TNF-α mRNA levels [32]. In a study utilising bronchoscopy, e-cigarette users had inflammatory signals between those of smokers and never-smokers, particularly for airway IL-1β, IL-6 and interferon (IFN)-γ [62]. In a study utilising induced sputum and blood samples, e-cigarette users had significant changes in gene expression, but less so and different to those seen in cigarette smokers, suggesting that e-cigarette use may not cause as many health effects as smoking, but those effects will be different to those caused by smoking [63].

Nicotine and flavourings have been shown to potentiate the pro-inflammatory effects of e-cigarette aerosol [34, 44]. Lerner et al. [31] noted increased production of IL-8 by human-derived fibroblasts exposed to cinnamon flavoured e-cigarette aerosol in vitro compared with unflavoured aerosol, and increased production of IL-6 and IL-8 by human airway epithelial cells exposed to tobacco-flavoured e-cigarette aerosol. Been et al. [43] also found that flavourings and nicotine significantly potentiated inflammation, with “mint” and “mango” flavourings having the largest effect. Finally, Moshensky et al. [58] found that nicotine, “mint” and “mango” flavours led to altered inflammatory transcriptomes in the lungs, with notable gene expression changes in GTPases (nicotine), mucins (“mint”), chemokine (C-C motif) ligand-6 (“mango”) and transforming growth factor-β receptors (nicotine and “mango”).

In summary, the majority of available data suggest that e-cigarette aerosol can induce acute and chronic inflammation in the lungs in vivo and in vitro, although less so than combustion cigarette smoke. Addition of cinnamon, tobacco, mint and mango flavouring in e-liquids may exacerbate inflammatory responses. Lung inflammation is central in the pathogenesis of most chronic lung diseases, including COPD, asthma, interstitial lung diseases and lung cancer. The exacerbation of lung inflammatory processes with e-cigarette use therefore has the potential to drive and exacerbate associated clinical disease including COPD, asthma, interstitial lung disease and neoplastic diseases. More research is needed in these areas, but studies thus far suggest that e-cigarette use might worsen asthma pathogenesis by increasing inflammatory cell recruitment to the lungs and increase goblet cell hyperplasia [64].

Impact of e-cigarettes on antipathogen immune response

Available epidemiological data suggest that the incidence and severity of acute respiratory infections may be increased in e-cigarette users and particularly in dual users as compared to their combustion-only or nonsmoking counterparts [65, 66]. Independent in vitro studies suggest that e-cigarette aerosol results in a dysfunctional immune response against both viral pathogens such as influenza A, human rhinovirus and respiratory syncytial virus, as well as bacterial pathogens such as Streptococcus pneumoniae, Staphylococcus aureus and Klebsiella pneumoniae (figure 3) [67, 68].

In models of viral infection, increased inflammatory markers and increased morbidity and mortality are seen. Primary small airway epithelial cells at air–liquid interface secrete more IL-8, CXCL-10 and IFN-β in response to influenza A virus infection when exposed to e-cigarette aerosol [69]. A mechanism for impaired host defence due to e-cigarette aerosol may be reduced production of SPLUNC1, a lipid-binding protein important for innate immune responses in the upper airways. Specifically, e-cigarette aerosol was found to inhibit SPLUNC1 expression and promote human rhinovirus infection in primary human airway epithelial cells [50]. The addition of nicotine to the e-liquid exacerbated these effects. Similarly, e-cigarette-exposed mice demonstrate more weight loss, lung oedema, IFN-γ and TNF-α expression, viral titres and mortality after intranasal infection with influenza A virus than do control counterparts [57, 70].

Independent studies suggest that e-cigarette aerosol exposure additionally increases susceptibility to bacterial infections. Zhang et al. [71] challenged C57BL/6J mice with a sublethal intranasal dose of K. pneumoniae. Mice pre-exposed intranasally to e-liquid distillate from JUUL pods had significantly more TNF-α, IL-6, macrophage inflammatory protein-1α and IL-17 in the airway, a higher wet-to-dry ratio in the lungs and greater acute lung injury scores than control mice [71]. The authors proposed increased intracellular calcium (Ca2+) levels as a mechanism for increased e-liquid-induced inflammation in infected animals. In addition, impaired pulmonary bacterial clearance (S. pneumoniae) was found in mice exposed to e-cigarette aerosol for 2 weeks prior to infection. This defective bacterial clearance was thought to be partially due to reduced phagocytosis by alveolar macrophages in these e-cigarette-exposed mice [70].

E-cigarette aerosol has been reported to enhance the virulence of pathogenic agents. Specifically, pre-treatment of Staph. aureus with e-cigarette extract enhanced biofilm formation, expression of virulence genes, resistance to human antimicrobial peptide LL-37 and adherence and invasion of epithelial cells by bacteria particles [25]. Another study suggests that the flavouring additives can play a key role: immune function of primary human alveolar macrophages, neutrophils and natural killer cells was impaired in the presence of a cinnamaldehyde flavouring, with or without other common components of e-cigarette aerosols [72].

Interestingly, despite reports of increased incidence and severity of clinical acute respiratory infections related to e-cigarette use, two separate studies have noted that the composition of the human oral microbiome was impacted by e-cigarette use [73, 74], while the lung microbiome itself was unchanged [74]. Taken together with the in vitro data described earlier, this suggests e-cigarette use negatively impacts the antipathogen immune response in the face of both bacterial and viral infectious insults.

Impact of e-cigarettes on mucociliary function

E-cigarette use appears to alter mucociliary clearance by impacting both airway hydration and ciliary function (figure 3). A study investigating protease content (predominantly neutrophil-derived) in bronchoalveolar lavage fluid samples from smokers, e-cigarette users and nonusers demonstrated an increase in the proteolytic activation of epithelial sodium channels in vitro and resultant airway epithelial cell dehydration in e-cigarette and combustion tobacco users [75, 76]. Interestingly, e-cigarette and tobacco smoke exposure appeared to have similar impact, unlike cytotoxicity and inflammation, in which tobacco smoke caused more injury than e-cigarette aerosol.

In addition to the accumulation of proteases, e-cigarette aerosols can directly alter mucus viscosity by impeding channel function and mucin content. Lin et al. [77] demonstrated rapid changes to channel function (including cystic fibrosis transmembrane conductance regulator, Ca2+-activated chloride channels, and sodium channels) after in vitro exposure to e-cigarette aerosols. Interestingly, nonvapourised e-liquid did not induce these changes, indicating that thermal degradation products of e-liquids may be impacting ion transport. Several studies that collected samples via bronchoscopy or used sputum-based proteomics in humans showed alterations in secreted airway products [78, 79]. For example, several mucins (important regulators and building blocks of mucus viscosity) are increased in e-cigarette users and traditional cigarette users compared to nonsmoking controls [78]. Other secreted products discussed in more detail elsewhere, including neutrophil elastase and matrix metalloproteinases, are elevated in e-cigarette users more than in nonsmokers and combustion cigarette users.

Nicotine has been shown to worsen this mucociliary dysfunction. For example, mice exposed to aerosol from e-liquid containing PG with nicotine for 3 weeks (20 min·day−1) had reduced mucociliary clearance compared to mice exposed to aerosol from e-liquid that contained PG only [80]. Similarly, adding nicotine to the e-liquid reduced tracheal mucus velocity in sheep in vivo and increased airway surface liquid dehydration and mucus viscosity in human bronchial epithelial cells in vitro in a dose-dependent manner [81]. Nicotine may negatively impact mucociliary clearance by activating TRPA1 (transient receptor potential cation channel subfamily A member 1), leading to higher intracellular Ca2+ levels [81]. Notably, the flavouring cinnamaldehyde activates TRPA1, increasing intracellular Ca2+ levels in primary cells [82], probably contributing to its adverse effects.

Even in the absence of nicotine, e-cigarette aerosols can impact mucociliary clearance. For example, a 5-day exposure to either PG-only aerosol or VG-only aerosol increased mucus concentration of tracheal secretions in sheep [51, 83]. Likewise, exposure to PG-only aerosol decreased ciliary beating and increased mucus concentrations in human bronchial epithelial cells in vitro, probably by disrupting the function of large conductance, Ca2+ and voltage-activated potassium channels [83].

In summary, consistent in vitro and in vivo data suggest that e-cigarette aerosol impedes mucociliary function, and the nicotine in e-liquid may potentiate these effects. There is evidence to suggest that e-cigarettes and combustion tobacco products cause similar levels of mucociliary dysfunction. Impaired antipathogen immune responses (summarised earlier) and reduced mucociliary function can increase susceptibility to lung infections. These effects may be especially relevant to patients with bronchiectasis, chronic bronchitis and COPD, and to immunocompromised individuals.

Impact of e-cigarettes on oxidative stress and DNA damage

E-cigarette aerosol can induce oxidative stress that contributes to DNA damage (figure 3). In vitro, e-cigarette aerosol activates oxidative stress reporter dyes in cell-free systems [44] and in cell lines [84, 85]. In agreement, the prototypical marker of oxidative stress, i.e. hydrogen peroxide, is increased in cell lines and primary human bronchial epithelial cells exposed to e-cigarette aerosol in submerged culture [33] or air–liquid interface [86, 87]. Notably, cinnamon-flavoured e-liquids induced more oxidative stress than butter-flavoured e-liquids [87].

Furthermore, e-cigarette exposure activates oxidative stress response pathways. For example, e-cigarette extracts induce NAD(P)H quinone dehydrogenase (NQO)1 in primary human lung fibroblasts and haem oxygenase 1, glutamate-cysteine ligase modifier, glutamate-cysteine ligase catalytic subunit and glutathione peroxidase 2 in primary human epithelial cells [72, 88]. Similarly, e-cigarette extract reduces glutathione, a tripeptide molecule that neutralises reactive oxygen species (ROS), in various cell lines [24, 85].

The antioxidant protein DJ1, an important mediator against cigarette smoke-induced lung injury, may also protect against e-cigarette-induced lung injury [28]. Specifically, DJ1 knockdown increases ROS accumulation after a 1-h exposure to e-cigarette aerosol, and DJ1-KO mice have reduced oxidative phosphorylation after e-cigarette aerosol exposure [28].

In vivo, independent studies have detected increased oxidative stress due to e-cigarette aerosol exposure. For example, mice exposed to e-cigarette aerosol for 2 weeks had increased levels of lipid peroxidation in lung homogenates [70]. Similarly, rats exposed to e-cigarette aerosol for 4 weeks had increased nitroxide free radicals and decreased expression of antioxidant mediators catalase, NQO1 and superoxide dismutase [89]. In contrast, one study did not detect increased oxidative stress with e-cigarette aerosol exposure as assessed by dihydroethidium (DHE) staining [32]. DHE staining is a less sensitive method to detect oxidative stress and may explain the negative findings of this study.

Been et al. [43] assessed the impact of flavourings on oxidative stress. Serum malondialdehyde (MDA) levels were increased in mice after 3-day exposure to Virginia tobacco-flavoured JUUL pods, but not mango- and mint-flavoured pods (all 5% nicotine). Similarly, mice exposed to e-cigarette aerosol with nicotine and tobacco flavouring had increased markers of oxidative stress in lavage fluid and lung homogenate, including MDA and protein carbonyl levels, compared to vehicle control [90]. These studies suggest that tobacco flavouring and nicotine in e-liquid may potentiate oxidative stress.

Oxidative stress can induce DNA damage. In vitro, e-cigarette extract promotes oxidation and fragmentation of DNA as assessed by 8-oxo-2′-deoxyguanosine (8-oxo-dG) levels [31, 85]. In vivo, mice exposed to e-cigarette aerosols (2 h per day for 8 weeks) had increased plasma 8-oxo-dG levels [91] and increased DNA damage by Comet assay [89]. Furthermore, mint and tobacco-flavouring increased serum 8-oxo-dG levels compared to PG:VG control after a 3-day exposure [43]. Finally, Lee et al. [92] reported an increase in DNA adducts and decreased DNA repair capacity in the lungs of mice exposed to e-cigarette aerosol from e-liquid containing PG:VG and nicotine for 12 weeks.

DNA damage can initiate carcinogenesis. Zahedi et al. [93] reported increased epithelial-to-mesenchymal transition, an early marker of carcinogenesis, after exposure of lung epithelial cells in air–liquid interface to e-cigarette aerosol, particularly those with menthol flavourings. In a long-term murine model, lung adenocarcinoma developed in 22.5% of mice exposed to e-cigarette aerosol containing nicotine for 54 weeks versus 0% of mice exposed to aerosol from PG:VG only and 5% of mice exposed to ambient air [92].

In summary, most in vitro and in vivo studies suggest that e-cigarette use induces oxidative stress in the lung, causes DNA damage, and probably increases the risk of lung cancer. Nicotine seems to potentiate these changes, as may certain flavourings such as tobacco and menthol. Unfortunately, given the long latency of lung cancer with most inhalational exposures, such as traditional cigarette smoke, it is likely to be many years before epidemiological studies can assess lung cancer risk reliably in e-cigarette users.

Impact of e-cigarettes on matrix remodelling and emphysema

Investigation on the impact of e-cigarette use on matrix remodelling and emphysema is at a preliminary stage, particularly for human studies. There are no data to suggest increased radiographic emphysema in e-cigarette users compared to nonusers. However, this lack of evidence is perhaps unsurprising, as emphysema develops after many years/decades of traditional cigarette use, while e-cigarette use has become popular only recently. Nonetheless, it has been shown that matrix metalloproteases are increased the sputum and bronchoscopically sampled airway tissue from e-cigarette users [78, 79]. Furthermore, two animal studies reported histological evidence of emphysema after 6 weeks and 4 months of exposure to aerosol from unflavoured e-liquid [54, 61]. In one of these studies, the development of emphysema was conditional on the presence of nicotine in the e-liquid [54]. A third study did not detect emphysema in mice despite 4 months of exposure, probably due to the much lower aerosol dose [57].

There is a need for more studies on the impact of e-cigarette aerosol on matrix remodelling and emphysema, standardisation of animal models and examination of the role of additives and flavourings.

Impact of e-cigarettes on airway hyperresponsiveness

E-cigarette aerosol induces airway hyperresponsiveness in animal models (figure 3). Specifically, e-cigarette aerosol increased bronchoconstriction after methacholine challenge in mice [54, 90, 94]. Similarly, a single puff of e-cigarette aerosol was sufficient to stimulate vagal bronchopulmonary C-fibres and cause transient bronchoconstriction in anaesthetised guinea pigs, effects that were reversed with anticholinergics [95]. These findings suggest that e-cigarette aerosol stimulates sensory fibres leading to increased vagal tone and bronchoconstriction.

Nicotine-containing e-cigarette aerosol can alter mucin production and airway eosinophilia. For example, nicotine-containing e-cigarette aerosol increased the production of a mucin that causes airway obstruction in asthma (MUC5AC), while nicotine-free aerosol did not [54]. Allergen challenge can modulate the effect of nicotine. Specifically, after dust mite challenge, nicotine-containing e-cigarette aerosol reduced airway eosinophils, whereas nicotine-free aerosol did not [94]. Nicotine may exert these effects by activating the α-7-nicotinic receptor and downstream protein kinase Cα and extracellular regulated kinase signalling [54, 96].

E-liquid flavourings can impact airway hyperresponsiveness. For example, tobacco-flavoured e-cigarette aerosol caused similar airway hyperresponsiveness as traditional cigarettes, whereas nonflavoured aerosol did not [90]. Furthermore, cinnacide-flavoured aerosol reduced airway eosinophils; “black licorice”-flavoured aerosol increased macrophages; while “kola/banana pudding”-flavoured aerosol did not alter airway eosinophil numbers in mice [94]. These data suggest that individual flavouring compounds exert distinct biological effects on the airway, that require further investigation.

Therefore, there is evidence from animal models that e-cigarette aerosol can induce bronchoconstriction and more limited evidence that it can alter airway mucin production and airway eosinophilia. These data suggest that e-cigarette use can provoke or worsen asthma and induce bronchoconstriction in individuals with other kinds of airway diseases, such as COPD. The role of nicotine and flavouring compounds in modulating these responses needs further investigation.

How the introduction of e-cigarettes can impact tobacco-related lung disease morbidity and mortality in the community: the paradox of the “safer cigarette”

Although the available literature has significant limitations, it suggests that puff-for-puff, e-cigarette aerosol is less harmful to the lungs than combustion cigarette smoke. Therefore, will the introduction of e-cigarettes lead to a major reduction in tobacco-associated lung disease morbidity and mortality in the community? Unfortunately, not necessarily, because multiple factors can mitigate harm reduction due to e-cigarettes (figure 4).

FIGURE 4
FIGURE 4

Phenomena that will probably erode some of the potential gains from the lower puff-for-puff toxicity of e-cigarette aerosol compared with combustion cigarette smoke. The proportions of various subgroups in this figure, i.e. combustion cigarette smokers, quitters, e-cigarette users, dual users, etc. are hypothetical and for visual representation only.

First, evidence suggests that e-cigarettes can be a precursor to traditional cigarette use, particularly in young or first-time nicotine users [97–101]. For example, young individuals are more likely to initiate e-cigarette use than to smoke combustion cigarettes, due to their perceived safety. Once accustomed to e-cigarettes and addicted to nicotine, these individuals have 3.5 to four times higher odds of transitioning to smoking combustion use [102, 103].

E-cigarettes can serve as “re-entry” devices [104]: individuals who use e-cigarettes to quit combustion cigarettes are more likely to relapse to combustion cigarette use than those who quit altogether. Furthermore, smokers may use e-cigarettes to complement rather than replace combustion cigarettes. This concept is supported by the emergence of dual use, i.e. simultaneous combustion and e-cigarette use [105, 106].

Finally, we have only scratched the surface in understanding the pulmonary toxicity of e-cigarettes, and there are probably multiple toxicities that remain undiscovered [107, 108]. Heterogeneity in the type of device/composition of the e-liquid, lack of standardisation of in vitro and in vivo models, and lack of large human cohorts of e-cigarette users remain the most significant challenges to unravelling the toxicities of e-cigarettes. E-cigarette use has become popular only in recent years, and it may take many more years before long-latency diseases such as emphysema and lung cancer become evident in e-cigarette users. Therefore, it is important to use model systems and biomarkers that can predict these risks early before they become widespread.

Taken together, the gateway effect, re-entry effect, dual-use and known and unknown toxicities constitute the paradox of the safer cigarette (figure 5). The recent introduction of nicotine salt-containing fourth-generation devices will likely exacerbate this paradox, because the higher rate of nicotine delivery will enhance nicotine dependence and potential for toxicity, as described earlier.

FIGURE 5
FIGURE 5

The paradox of the safer cigarette.

Summary

The basic science data on the pulmonary effects of e-cigarettes is preliminary and evolving rapidly. Independent studies suggest that e-cigarette aerosol is cytotoxic to pulmonary cells, induces acute and chronic inflammation, impairs immune responses against viral and bacterial pathogens, impairs mucociliary clearance, induces oxidative stress, causes DNA damage and increases airway hyperresponsiveness in vitro and in vivo. Adding nicotine to the e-liquid increased mucociliary dysfunction, oxidative stress, emphysema and airway hyperreactivity. In preliminary studies, flavouring compounds have been implicated in lung damage induced by e-cigarettes. Specifically, cinnamon, tobacco and mint/menthol flavourings enhanced cytotoxicity and induce lung inflammation compared with other flavourings or the absence of flavouring. In addition, cinnamon flavourings have been found to impair antipathogen immune responses, reduce mucociliary clearance and enhance oxidative stress. Similarly, tobacco flavouring has been found to induce oxidative stress, airway hyperresponsiveness and DNA damage. Finally, mint/menthol flavouring has been associated with increased DNA damage. The available data suggest that puff-for-puff, e-cigarette aerosol is less harmful than combustion cigarette smoke in terms of cytotoxicity and lung inflammation. This reduced harm of e-cigarettes may not fully translate into reduced morbidity and mortality in the community due to the gateway effect, re-entry effect, dual-use and known and unknown toxicities of e-cigarettes. In aggregate, we label these phenomena the paradox of the safer cigarette.

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Acknowledgement

The University of Pittsburgh holds a Physician-Scientist Institutional Award from the Burroughs Wellcome Fund (K. Allbright).

Footnotes

  • Conflict of interest: K. Allbright reports grants from Burroughs Wellcome Fund and T32 (5T32HL007563-35), outside the submitted work. L.E. Crotty Alexander reports grants from NIH NHLBI R01, NIH NHLBI K24 and VA Merit Award, advisory board participation with Regeneron, and leadership roles with CHEST and ALA San Diego, outside the submitted work. M. Zhang reports support for the present article from Regeneron Pharmaceuticals. K.H. Benam has received grants from the US Food and Drug Administration, US National Institutes of Health, US Department of Defense and the Gordon and Betty Moore Foundation, royalties from Emulate Inc., consulting fees from Pneumax LLC, has received invited speaker honorarium from Colorado State University, has multiple pending and issued patent applications, has non-significant personal investments in a number of publicly traded companies, and is the founder of Pneumax LLC. The remaining authors have no potential conflicts of interest to disclose.

  • Support statement: This work was supported by the Pittsburgh Foundation, BREATHE PA, National Heart, Lung, and Blood Institute (grant: R01HL153400) and the Burroughs Wellcome Fund. Funding information for this article has been deposited with the Crossref Funder Registry.

  • Received May 13, 2022.
  • Accepted March 16, 2024.

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The paradox of the safer cigarette: understanding the pulmonary effects of electronic cigarettes
Kassandra Allbright, John Villandre, Laura E. Crotty Alexander, Michael Zhang, Kambez H. Benam, John Evankovich, Melanie Königshoff, Divay Chandra
European Respiratory Journal Jun 2024, 63 (6) 2301494; DOI: 10.1183/13993003.01494-2023
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