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Review

The Role of ROS in Electronic Cigarette- and Heated Tobacco Product-Induced Damage

by
Nancy E. Gomez
1,† and
Silvia Granata
2,*,†
1
School of Medicine, University of Nottingham, Nottingham NG7 2RD, UK
2
IRCCS Neuromed, Via Atinense, 18, 86077 Pozzilli, Italy
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Oxygen 2024, 4(4), 363-376; https://doi.org/10.3390/oxygen4040022
Submission received: 31 August 2024 / Revised: 20 September 2024 / Accepted: 23 September 2024 / Published: 25 September 2024
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Abstract

:
The success of heated tobacco products (HTPs) and electronic cigarettes (e-cigs) has been largely attributed to their ability to mimic the gestural experience of traditional cigarette smoking, while being perceived as a safer alternative due to the absence of combustion, as well as to their appeal, particularly among younger populations. Despite the initial idea that these new devices were harmless, recent literature reveals a concerning expanding body of evidence on their potential toxicity. Thus, this literature review aims to elucidate the mechanisms by which reactive oxygen species generated by HTPs and e-cigs induce oxidative stress and inflammation and the subsequent biological and health consequences, in order to raise awareness on the significance of addressing the potential toxicological effects associated with these devices, which are commonly believed to be safe.

1. Introduction

Electronic nicotine delivery systems (ENDS) or electronic-cigarettes (e-cigs) have been developed to create an alternative to conventional cigarettes (CCs) [1], since more than 8 million people per year die due to the tobacco epidemic [2]. These devices can be divided into liquid e-cigs, which vaporize a liquid, and heated tobacco products (HTPs), which claim to heat tobacco by avoiding the combustion phenomenon [3]. A schematic representation of liquid e-cigs and HTPs is shown in Figure 1. Briefly, there is a variety of liquid e-cigs, but they all share some basic components: the drip tip, or spout, an instrument on which the lips rest to inhale the vapor; a rechargeable lithium-ion battery; a tank containing the e-liquid; and an atomizer to produce the mainstream. Most importantly, some liquid e-cigs are customizable: as a matter of fact, users can pick the flavorings and the ratio of liquid components (percentage of glycerol, propylene glycol and nicotine) [3]. On the other hand, HTPs are very different from e-cigs: they do not vaporize flavored liquids, but heat tobacco sticks by an electronic blade or an induction heating chamber with a controlled average temperature of 300–350 °C, as opposed to the 900 °C of a traditional cigarette [4]. The success of these devices was mainly determined by the fact that they make it possible to mimic, from the point of view of gestures, the natural behaviour of the addict, and they were believed to be harmless due to the absence of the combustion process [5]. The perception of harmlessness has been indirectly reinforced by the recent marketing authorization granted by the Food and Drug Administration (FDA) as “Modified Risk Tobacco Products” (MRTP) to the HTP known as IQOS® (Philip Morris International, Stamford, CT, USA) [6], which has been granted as “modified exposure” and not “modified risk” since there was not enough evidence for this order [6]. The World Health Organization (WHO) and public health bodies have issued statements emphasizing that HTPs and ENDS are not risk-free. Indeed, the WHO emphasizes that both tobacco products and ENDS pose risks to health, with the safest approach being to not use either [7].
To date, tobacco smoke is commonly known as one of the risk factors for several diseases (such as respiratory, cardiovascular, and cancer) that can be easily removed [7]. Considering their appeal, especially among the young, it is of primary importance to understand whether ENDS still represents a health risk factor. Despite the initial idea that these new devices were harmless, recent literature presents an expanding body of evidence on their possible toxicity [8,9,10,11]. However, various surveys have indicated that users have a common belief that ENDS are less harmful and less addictive than CCs and erroneously believe that they are consequently safe to use [12,13].
The consumption of e-cigs and HTPs has been associated with an overproduction in radical oxygen species (ROS) [8,14], which results in oxidative stress (OS) and plays a significant role in the occurrence of macromolecular damage that can lead to the onset of diseases [15]. Generally, ROS are required for the efficient functioning of living organisms, while they can be detrimental under certain situations [16]. Indeed, under physiological circumstances, radicals are formed in a normal endogenous metabolism during the processes of cellular respiration and enzymatic reactions, such as the ones catalyzed by cytochrome P450 monooxygenases, cyclooxygenases, lipoxygenases, xanthine oxidase, and mitochondrial respiration [16]. However, it is also possible for free radicals to instead be generated after the exposure to exogenous sources, which mostly include ionizing and solar radiation, pollution, drugs, and inhaled hazardous chemicals, such as those generated by CC smoke [16,17]. Thus, the present literature review aims to examine and elucidate the mechanisms by which ROS generated by HTP and e-cig use cause OS and to explore the subsequent biological and health implications of this damage.

2. ROS Generation in HTP and E-Cig Consumption

Early research about HTPs and e-cigs has focused on investigating the production of harmful thermal breakdown products which could endanger users’ and bystanders’ health. Tobacco-specific nitrosamines (TSNAs), metals, polycyclic aromatic hydrocarbons (PAHs), volatile organic compounds (VOCs), carbonyl compounds, and aldehydes are among them [18,19]. However, one piece of literature also aimed to analyze the possible presence of ROS in their smoke [20,21,22,23]. The study does, indeed, provide data on the concentration of ROS generated by these devices (Table 1).
Table 1. Summary of ROS content (mean) in a CC, e-cig, and HTP.
Table 1. Summary of ROS content (mean) in a CC, e-cig, and HTP.
DeviceNmol H2O2/SessionRadicals/Puff
CC46.83 [23]>1016 [24]
E-cig25–35 [20]5.6 × 1013 [22]
HTP (IQOS)6.26 [23]N.R.
N.R. not reported.
Specifically, Lerner et al. found that an e-cig aerosol generates significant levels of ROS, measuring them using the cell-free dichlorofluorescein diacetate (DCFH-DA) assay [20]. In fact, this study reported a concentration of 25 to 35 nmol H2O2 produced by two different e-cig devices, the blu e-cig and eGO Vision spinner, respectively [20]. Furthermore, Goel’s research has used electron paramagneticresonance (EPR) to investigate whether an e-cig aerosol contains radicals [21]. His research showed an average of 5.6 × 103 radicals per puff, which is a 100- to 1000-lower concentration than CCs (>106 radicals/puff) [24], but still 10-fold greater than those found in air pollution [21,25]. Another study focused on evaluating only the hydroxyl radicals (•OH) since it is believed to be the most hazardous radical [22]. •OH was found in the aerosol of e-cigs and its concentration changed depending on the e-liquid composition, namely, the presence of flavors determined a higher concentration [22]. On the other hand, ROS production in HTPs is still poorly documented. In fact, we found only one study that focused on this evaluation in IQOS and compared it to the production of CCs, using the same regime (ISO), and found that the HTP studied generated a lower concentration of nmol of hydrogen peroxide than the CCs [23].
Even though the concentration appears to be reduced in the new devices compared to CCs, they still increase ROS exposures and result in potential health problems. Moreover, the exposure to the other toxicants in ENDS smoke boosts ROS levels in cells [9,14,26], potentially worsening the scenario. Indeed, their increase may result in inflammation and DNA damage, as well as the activation of signaling or metabolic pathways associated with an increased risk of cancer [9,11].
ROS increase following ENDS exposure has been widely reported (Table 2) in primary target organs not only in vitro or in vivo but also in clinical research [11,27,28,29]. Whenever there is an increase in radical species, a perturbation in the homeostasis follows, and the cells must react to minimize the related damage and return to the status quo. However, it is not always possible to counteract efficiently, and the balance is shifted towards ROS formation [30]. Thus, the ROS boost is followed by an imbalance in the ROS/antioxidant defences ratio, causing OS [30]. Namely, sometimes researchers investigate the presence of OS markers in order to confirm the ROS increase and its related damage, especially when it is difficult to directly analyze the ROS content, as in humans [31,32]. Chatterjee et al., as a matter of fact, have reported both in vitro and clinical study: in the first part, they revealed a boosted ROS in human pulmonary microvascular endothelial cells (HPMVECs), as well as ICAM-1, which is a marker of inflammation [32,33]. ICAM-1 is a cell surface glycoprotein that belongs to the Ig family and its expression is upregulated by inflammatory stimuli [33]. In this case, e-cig exposure caused an increase in ROS, which is correlated to OS, and an inflammatory state [32]. Then, they studied a cohort of e-cig smokers and healthy nonsmokers to evaluate the effects of e-cig exposure in their blood samples. C-reactive protein and ICAM-1 were detected as increased in all the subjects following e-cig exposure, confirming that these devices also determine inflammation in humans. Nitric oxide (NO) metabolites, on the other hand, were found with reduced levels, probably because NO reacts with ROS, which are highly produced in this condition [32]. This finding is associated with endothelial dysfunction, which might be present in smokers [34], and has also been observed in another study conducted by Carnevale [31].
The increase in ROS production has also been observed in human bronchial epithelial cells (NHBE), BEAS-2B and A549 cells [11,26,35,36], but also in oral squamous cell carcinoma (OSCC) [37] and Kupffer cells [27] following either e-cigs or HTPs. These in vitro studies have also shown a reduction in the total glutathione (GSH) [11,26,35], which is consistent with the protective role that GSH plays against ROS [38]. This reduction has also been observed in vivo in alveolar macrophages [39] and in the liver [40]. An imbalance in the GSH-related enzyme system has also been reported in A549 cells [36] and in vivo in the lung [9] and in the alveolar macrophages [39], demonstrating a perturbation in the GSH-related antioxidant defences due to the threat of radicals.
Table 2. Studies evaluating ROS production and related OS damage caused by e-cigs and HTPs. ⭡ = increased; ⭣ = decreased.
Table 2. Studies evaluating ROS production and related OS damage caused by e-cigs and HTPs. ⭡ = increased; ⭣ = decreased.
ReferencesDeviceType of StudyExposure in…Key Findings
Rubenstein et al. 2015 [27]E-cigin vitroKupffer cells ⭡ ROS
⭡ xanthine oxidase activity
Sussan et al. 2015 [28]E-cigin vivoLung⭡ lipid hydroperoxides
Carnevale et al. 2016 [31]E-cigclinicalHuman subjects⭡ NOX2-derived peptide, 8-iso-prostaglandin F2α
⭣ NO bioavailability
⭣ vitamin E levels
El Golli et al. 2016 [29]E-cigin vivoLiver⭡ lipid hydroperoxides, thiols
⭣ SOD, catalase activity
Chatterjee et al. 2018 [32]E-cigin vitro



clinical		HPMVEC (pulmonary endothelium)

Human subjects		⭡ ROS
⭡ ICAM-1


⭡ C-reactive protein
⭡ ICAM-1
⭣ NO metabolites
Lee et al. 2018
[11]		E-cigin vivo



in vitro		lung, bladder, heart



BEAS-2B cells, bladder cells		⭡ DNA damage
⭣ repair protein XPC and OGG1/2


⭡ DNA damage
⭣ repair protein XPC and OGG1/2
Cirillo et al. 2019 [9]E-cigin vivolung⭡ ROS
⭡ lipid hydroperoxides, carbonylated proteins
⭡ xanthine oxidase, GSSG reductase activity
⭡ CYP1A1, CYP2E1, CYP2B1/2. CYP2A1/2 activity (CYP450)
⭣ FRAP, catalase, SOD, CYP3A1/2 activity
Pearce et al. 2020 [26]E-cigin vitroNHBE (bronchial epithelium)⭡ ROS
⭡ DNA damage
⭣ total GSH content
⭣ metabolic capacity
Vivarelli et al. 2021 [14]HTPin vivolung⭡ ROS
⭡ NQO1, catalase activity
⭡ lipid hydroperoxides, carbonylated proteins
⭡ CYP1A1, CYP2E1, CYP2B1/2. CYP2A1/2 activity (CYP450)
⭡ p38, ERK1/2, JNK expression
⭡ DNA damage
⭣ FRAP, UDPGT activity
⭣ NRF2 expression
Sawa et al. 2022 [39]HTPin vivoalveolar macrophages⭡ GSSG/total GSH
⭣ reduced GSH content
Muratani et al. 2023 [35]HTPin vitroNHBE (bronchial epithelium)⭡ ROS
⭣ total GSH content
Begum e al. 2023 [36]E-cigin vitroA549 (alveolar epithelium)⭡ ROS
⭡ cytosolic NADH oxidase, SOD, catalase, and GSH-Px mRNA expression
Granata et al. 2023 [40]HTPin vivo liver⭡ ROS
⭡ mitochondrial mass, carbonylated proteins, lipid hydroperoxides
⭡ DT-diaphorase, catalase, xanthine oxidase, UDPGT activity
⭡ CYP1A1, CYP2E1, CYP2B1/2. CYP2A1/2 activity (CYP450)
⭡ p38 expression
⭣ total GSH content
⭣ NRF2 expression
Kagemichi et al. 2024 [37]HTPin vitroOSCC (oral squamous cell carcinoma)⭡ ROS
⭡ p38 phosphorylation
⭡ intracellular Ca2+ concentration

3. Oxidative Stress Related to ENDS Exposure

OS is a consequence of increased ROS and/or the reduced physiological activity of the antioxidant defence system [30]. Hence, it might be considered as a perturbance in the homeostasis of oxidants and antioxidants, allowing a switch towards the oxidants meaning that antioxidant enzymes (such as catalase, xanthine oxidase, and superoxide dismutase) and molecules (such as NRF2 or NfkB) fail to protect the cells (Figure 2). This switch translates into molecular damage [41].
OS-related damage can be determined through a plethora of assays, as it can be confirmed by the co-presence of more than one impaired molecule. One of the processes of oxidative damage is oxidation, namely, the oxidation of thiol groups in proteins, causing protein carbonylation [42]. Interestingly, protein carbonylation is assumed to be permanent [43], thus this process can lead to irreversible damage. Recently, protein carbonylation has been observed in in vivo studies involving e-cig and HTP usage [9,14,40], unveiling that ENDS concernedly cause this type of irreversible damage in cells. Together with carbonylation of proteins, another process linked to ROS generation is lipid peroxidation in membrane lipids, which leads to membrane degradation, caused by the hydroxyl radical [44]. Their increase has been reported in a plethora of studies, following both e-cig [9,29,44] and HTP [14,40] exposure.
OS is the primary cause of DNA damage since high levels of ROS can generate numerous insults to the genetic material, such as base substitutions and cross connections, leading to DNA strand breaks [45]. As a matter of fact, elevated levels of ROS following e-cigs and HTPs use have lately been reported to determine DNA oxidative damage [11,14,26]. This finding is of primary importance since these devices have been perceived as a safe option for health in contrast to CCs. However, these pieces of evidence suggest otherwise and show how ENDS might be hazardous for human health, probably as CCs are. DNA damage has been assessed by different assays in the reported studies. Lee [11] has investigated the formation of 1,N(2)-propano-2′-deoxyguanosine and O(6)-Methyl-2′-deoxyguanosine in lung, bladder, and heart tissue following e-cig exposure. The comet assay was performed in the Pearce study [26]: this assay aimed to detect single and double-stranded DNA breaks in cells [46] and showed how different e-cig devices can induce various levels of DNA breaks. On the other hand, the quantifying of two species of oxidized guanosine (8-hydroxy-2′-deoxyguanosine, and 8-hydroxyguanine) was used by Vivarelli et al. [14]. These markers not only indicate OS but also positively correlate with the risk of mutagenesis and carcinogenesis [47,48].
Furthermore, when talking about the ROS imbalance and OS, the cytochrome P450 (CYP450) family should also be discussed. In fact, it is the principal enzymatic set of phase I enzymes involved in the detoxification and bioactivation processes of most xenobiotics [49]. For each substrate molecule processed, one molecule of O2 is consumed and disrupting this cycle may result in the release of oxygen in the form of superoxide anion (O2•−) or hydrogen peroxide (H2O2) [50]. The above processes are significant because CYP450 enzymes may boost the amounts of ROS in cells, exacerbating OS damage to DNA, RNA, and proteins [50]. For these reasons, CYP450 modulations have been investigated in some studies [9,14,40]. Mostly, monooxygenases linked with CYP450 isoforms exhibit enhanced activity following ENDS exposure, along with high levels of ROS and other OS markers, such as protein carbonylation, lipid peroxidation, and DNA damage [9,14,40], confirming the hypothesis of a continuous “vicious” cycle of ROS production in smokers.
Last but not least, the mitochondria—which are known to be the powerhouses of the cell—are notably vulnerable to oxidative insult and might alter their physiological functionality [51]. Whenever there is an overproduction of ROS, mitochondrial damage may incur in cells, through dysfunctions of oxidative phosphorylation and changes in their morphology, finally leading to mitochondrial dysfunction [52]. As a matter of fact, mitochondrial dysfunction caused by the high levels of ROS following e-cig exposure has been reported by Emma et al. [53]. In addition, generally, mitochondrial dysfunction itself might determine alterations in the calcium influx, depletion of ATP, and opening of the mitochondrial permeability transition pore (mPTP) [52,54]. In fact, in their study, Kagemichi et al. observed an increase in ROS levels as well as the intracellular Ca2+ concentration, which might be associated with high levels of Ca2+ in mitochondria, determined by HTP exposure of OSCCs [37]. More importantly, these increases usually trigger death signaling resulting in apoptosis and tissue damage [55]. This finding is of importance since the ENDS exposure-related effect on these organelles can also have consequences at the tissue level, corroborating the health risks already associated with the use of these devices.

4. Inflammation

ENDS emit volatile carbonyls, ROS, furans, and metals, some of which are known to be toxic to the lungs. Indeed, their exposure drives the increased production of ROS, which induce apoptosis, mitochondria dysfunction, and protein inactivation, and induce cellular damage, respectively [56,57,58,59]. The use of e-cigs results in a number of adverse effects that may lead to inflammation in the lungs (Figure 3). Carnevale et al. [31] showed that e-cig use rapidly increased circulating markers of oxidative stress, including 8-isoprostanes, and increased activity of NOX2 compared to nonsmokers. NOX2 is an isoform of NADPH oxidase expressed in platelets and an important source of OS [60]. Furthermore, acute exposure to e-cig smoke has been observed to decrease the total and oxidized levels of lung GSH, which may impose OS that results in an inflammatory response [20].
Vaping of e-cigs can affect ROS production, whereby PAHs and other potentially harmful constituents found in e-cig vapor are oxidized, leading to increased ROS production [61]. The increased generation of ROS due to e-cig exposure further induces inflammatory responses, as observed in both human epithelial cells and murine models [20], and the main cells found to be recruited to the lungs during exposure to e-cig smoke include macrophages, neutrophils, eosinophils, and T cells [62,63,64,65]. Indeed, exposure to e-cigs stimulates epithelial cells and immune cells in the upper airway and lung to secrete proinflammatory cytokines including Interleukin (IL)-1 β, IL-6, IL-8 and TNF- α [20,63,66,67]. IL-6 and IL-8 are indicators of an ongoing inflammatory response in epithelial cells and monocytes, and IL-8 is a potent neutrophil attractant [56]. Exposure to e-cigs smoke results in an excessive production of ROS, inflammatory cytokines and chemokines that may induce an inflammatory state in alveolar macrophages within the lung [56]. Scott et al. 2018 [67] observed that both nicotine-free and nicotine-containing condensate induced a significant increase in ROS release from alveolar macrophages (AMs), suggestive of both nicotine-dependent and independent mechanisms being involved, and which leads to pulmonary epithelial damage and an influx of neutrophils to the site of injury. This study also observed significant upregulation of OS-related proteins in vapers, including MMP-9, which has been implicated in inflammatory lung diseases such as chronic obstructive pulmonary disease (COPD) [67]. E-cig exposure also activates neutrophils, leading to the degranulation of stored mediators and enzymes, oxidative bursts, and the release of neutrophil extracellular traps (NETs), which results in a significant increase in neutrophil elastase, proteinase 3, azurocidin-1, and myeloperoxidase [68]. Increased protease activity from exposure to e-cig smoke can damage the lung basement membrane and extracellular matrix, leading to emphysema [56]. Cell death further drives inflammatory pathways activated within the lungs. Serpa et al. [69] showed that exposure to e-cigs results in a mixture of apoptosis and necrosis in epithelial cells, where necrosis releases DAMPs that stimulate inflammation. The study also showed that macrophages exposed to e-cigs underwent pyroptosis, an inflammatory programme of cell death that results in the release of inflammatory cytokines. Exposure to e-cig vapor also increases the release of extracellular vesicles (EVs), small membrane-bound particles that play a key role in cell-to-cell communication, from various cell types, including endothelial, epithelial, and immune cells [70,71,72]. EVs released following exposure to e-cig vapor express markers from the cell of origin and can result in increased endothelial cell inflammation [70,71]. Similar to EVs released following exposure to traditional cigarette smoke [73,74,75], e-cig vapor-EVs carry various biomolecules and as such may function in the activation of cellular responses promoting inflammation.
Furthermore, e-cig vapor exposure also inhibits the antibacterial function of epithelial cells, macrophages, and neutrophils [66,76,77]. This establishes a favorable environment for pathogenic bacterial colonization and growth, resulting in chronic inflammation [55]. Additionally, airway epithelial cells from e-cig users were found to have a decreased expression of Toll-like receptor 3 (TLR3), suggestive of impaired viral immunity resulting from ENDS use [28,78]. Indeed, the infection of e-cig-exposed mice with influenza leads to increased lung inflammation and injury [28]. The inability to control the viral infection may lead to excessive lung inflammation in response to viral infection [28].
Systemic inflammatory responses can also be triggered by exposure to ENDS. Chatterjee et al. [32] showed that smoking-naïve healthy subjects had increased serum levels of ROS and ICAM-1 following e-cig challenge which returned to baseline levels after 6 h, suggesting that acute e-cig smoke inhalation leads to a transient increase in OS and inflammation. Indeed, this implies that e-cig vaping can adversely affect the vascular endothelial network, potentially driving the onset of vascular pathologies. Jackson et al. [79] showed that e-cigarette users had a significant increase in plasma immunoglubin E (IgE) levels compared to nonusers. IgE is key factor in allergic airway disease but also has a key role in non-allergic airway inflammation, and elevated IgE is indicative of type-2 inflammation [80]. Additionally, a study by Singh et al. [81] observed that ENDS users had a significant increase in inflammation markers and decrease in pro-resolving lipid mediators in plasma and endothelial dysfunction. The plasma levels of IL-1β, IL-6, IL-8, IL-13, IFN-g, MMP-9, and ICAM-1 were significantly higher in e-cig users compared to nonusers, whereas pro-resolving lipid mediators, resolvin D1, and resolvin D2 were significantly decreased [81].
Overall, e-cig smoke exposure results in increased ROS, pulmonary epithelial damage, increased cytokines and chemokines release, increased infiltration and activity of inflammatory cells, and DNA damage. It also causes impaired mucociliary clearance and reduced antibacterial and antiviral activity by many cells in the lung, which may result in chronic inflammation in the lung. Their exposure also drives systemic inflammation that can have detrimental effects on susceptible tissues.

5. Conclusions

The presence of ROS in ENDS can have detrimental health effects as it may lead to inflammation- and oxidative stress-related lung injury and diseases, including asthma, bronchitis, lung fibrosis, COPD, and lung cancer [82]. Inhaled ROS from these devices can also damage lung epithelial cells, impair ciliary function, and reduce the lungs’ ability to clear mucus and pathogens [83]. Previous studies have shown that acute exposure to ROS from e-cigs may cause respiratory symptoms, including coughing, wheezing, shortness of breath, and chronic bronchitis [20,84,85] and result in a decrease in the forced expiratory volume (FEV1) and FEV1/FVC, therefore potentially reducing the ability to breathe efficiently [83,86]. These effects may lead to the development of emphysema, chronic bronchitis and, consequently, COPD, and an increased susceptibility to infections. Furthermore, inflammation and OS caused by ROS lead to endothelial activation and dysfunction, leading to vascular disease [87,88]. A previous study by Chatterjee et al. [89] demonstrated that a single episode of vaping resulted in a significant increase in ROS production and a significant increase in C-reactive protein, soluble intercellular adhesion molecule, high-mobility group box 1 (HMGB1) and its downstream effector and the NLR family pyrin domain containing 3 (NLRP3) inflammasome compared to baseline values. These findings correlated with parameters of vascular function, suggestive of adverse impacts on vascular function [89]. Indeed, these effects are associated with an increased risk of atherosclerosis and cardiovascular diseases, including hypertension, coronary artery disease, and stroke [88]. ROS are also known to induce mutations and interfere with DNA repair mechanisms, thus causing DNA damage. Indeed, studies have shown that ENDS exposure can lead to DNA strand breaks and reduce repair activity in lung and bladder cells [11,14,58,90]. This in turn increases the risk of cancers in the lungs, mouth, throat, and other susceptible tissues and organs affected by ROS from e-cigs.
Overall, the existing evidence suggests that ENDS usage can determine an ROS increase and result in OS damage, which can lead to health effects ranging from acute respiratory effects to chronic conditions affecting the respiratory, cardiovascular, and other susceptible systems [14,31,32,40,55]. These effects highlight the importance of continued investigation into the potential risks associated with the use of e-cigs and HTPs, especially considering that these devices have been promoted as risk-free and healthier than traditional smoking [91]. However, over time, these claims are being questioned as their health risks become clear to the scientific community [69,86,89]. Therefore, it is of primary importance to thoroughly investigate the hazards associated with these devices to establish their long-term effects on the body and prevent unforeseen issues such as the emergence of EVALI (“E-cig or Vaping-Associated Lung Injury”) in 2019 [92,93].
To conclude, this review highlights how e-cig and HTP exposure increases ROS and related OS, along with triggering inflammatory responses and associated health implications. The aim is to raise awareness of the importance of studying the potential toxicological effects of these devices, which are often mistakenly perceived as safe.

Author Contributions

Conceptualization, S.G.; investigation, N.E.G. and S.G.; resources, N.E.G. and S.G.; writing—original draft preparation, N.E.G. and S.G.; writing—review and editing, N.E.G. and S.G. All authors have read and agreed to the published version of the manuscript.

Funding

This study received no external funding.

Acknowledgments

Silvia Granata wishes to relay a message for Mario Faro: “I am so lucky to have you by my side”. Figure 1, Figure 2 and Figure 3 were created with the use of BioRender.

Conflicts of Interest

The authors declare no conflicts of interest.

Abbreviations

AMsalveolar macrophages
CCconventional cigarette
COPDchronic obstructive pulmonary disease
DCFH-DAdichlorofluorescein diacetate
e-cig electronic-cigarette
ENDS Electron Nicotine Delivery System
EVALIE-cigs or Vaping Associated Lung Injury
EVsExtracellular Vesicles
FEV1forced expiratory volume
GSHglutathione
HMGB1high-mobility group box 1
HPMVECshuman pulmonary microvascular endothelial cells
HTPsheated tobacco products
ICAM-1intercellular cell adhesion molecule-1
ILinterleukin
IgE immunoglubin E
mPTPmitochondrial permeability transition pore
MRTPModified Risk Tobacco Products
NETsNeutrophil extracellular traps
NHBEhuman bronchial epithelial cells
NLRP3NLR family pyrin domain containing 3
OSoxidative stress
OSCCoral squamous cell carcinoma
ROSradical oxygen species
TLR3Toll-like receptor 3

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Figure 1. Schematic representation of some different types of ENDSs. At the top of the figure (A), there is a pen type of e-cig: it is cylindrical in shape and presents a visible tank or cartridge filled with e-liquid, and a mouthpiece at the top. On the bottom half of the figure (B), there are two representations of an HTP: a device that uses a heating blade (i) and one that uses induction heating (ii). Created in BioRender. (2024). BioRender.com/f51p346 (accessed on 24 September 2024).
Figure 1. Schematic representation of some different types of ENDSs. At the top of the figure (A), there is a pen type of e-cig: it is cylindrical in shape and presents a visible tank or cartridge filled with e-liquid, and a mouthpiece at the top. On the bottom half of the figure (B), there are two representations of an HTP: a device that uses a heating blade (i) and one that uses induction heating (ii). Created in BioRender. (2024). BioRender.com/f51p346 (accessed on 24 September 2024).
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Figure 2. Representation of the ROS increase loop. More ROS creates an imbalance in the oxidant/antioxidant ratio, which causes OS. Finally, OS increases the productions of ROS, exacerbating the imbalance and creating the vicious cycle. Created in BioRender. (2024). BioRender.com/y42y408 (accessed on 24 September 2024).
Figure 2. Representation of the ROS increase loop. More ROS creates an imbalance in the oxidant/antioxidant ratio, which causes OS. Finally, OS increases the productions of ROS, exacerbating the imbalance and creating the vicious cycle. Created in BioRender. (2024). BioRender.com/y42y408 (accessed on 24 September 2024).
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Figure 3. The use of e-cigs results in adverse effects that lead to inflammation in the lungs and systemically. E-cig exposure affects the production of ROS in the lungs and results in increased apoptosis of cells, DNA damage, recruitment and activation of inflammatory cells that release proinflammatory mediators, and decreased antibacterial and antiviral function, all of which drive inflammation in the lungs. Systemic effects include increased ROS and markers of inflammation, with decreased levels of pro-resolving lipid mediators. (↑ = increased; ↓ = decreased). Created in BioRender. (2024) BioRender.com/h45m504 (accessed on 24 September 2024).
Figure 3. The use of e-cigs results in adverse effects that lead to inflammation in the lungs and systemically. E-cig exposure affects the production of ROS in the lungs and results in increased apoptosis of cells, DNA damage, recruitment and activation of inflammatory cells that release proinflammatory mediators, and decreased antibacterial and antiviral function, all of which drive inflammation in the lungs. Systemic effects include increased ROS and markers of inflammation, with decreased levels of pro-resolving lipid mediators. (↑ = increased; ↓ = decreased). Created in BioRender. (2024) BioRender.com/h45m504 (accessed on 24 September 2024).
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Gomez, N.E.; Granata, S. The Role of ROS in Electronic Cigarette- and Heated Tobacco Product-Induced Damage. Oxygen 2024, 4, 363-376. https://doi.org/10.3390/oxygen4040022

AMA Style

Gomez NE, Granata S. The Role of ROS in Electronic Cigarette- and Heated Tobacco Product-Induced Damage. Oxygen. 2024; 4(4):363-376. https://doi.org/10.3390/oxygen4040022

Chicago/Turabian Style

Gomez, Nancy E., and Silvia Granata. 2024. "The Role of ROS in Electronic Cigarette- and Heated Tobacco Product-Induced Damage" Oxygen 4, no. 4: 363-376. https://doi.org/10.3390/oxygen4040022

APA Style

Gomez, N. E., & Granata, S. (2024). The Role of ROS in Electronic Cigarette- and Heated Tobacco Product-Induced Damage. Oxygen, 4(4), 363-376. https://doi.org/10.3390/oxygen4040022

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