Introduction

E-cigarettes are non-combustible electronic nicotine delivery devices that contain nicotine in a liquid vehicle of propylene glycol and vegetable glycerine along with a broad range of flavours (Stratton et al. 2018). The e-cigarette liquid (e-liquid) is then heated in a battery-powered device and inhaled. People use tobacco and e-cigarettes to get nicotine to the brain: conventional tobacco products and newer e-cigarette devices are highly efficient nicotine delivery systems. Tobacco smoking is declining because of multiple cultural factors, including bans on tobacco advertising and flavoured products and increased taxes (Wakefield et al. 2011; McNeill et al. 2017). In contrast, vaping is less regulated and has been increasing in popularity in many countries since these restrictions do not yet apply. Thus, a current challenge is to keep up with cultural changes both from scientific and public health perspectives in order to provide evidence-based research for the legislature. Indeed, research in this area is struggling to keep pace with a dynamic marketplace, escalating use and changing cultural perceptions. Whether or not e-cigarettes are safer than conventional tobacco smoking has been hotly contested, and their effects on neuronal function and underlying behaviours associated with e-cigarette use remain unclear. Similarly, their effects on the pulmonary system, the body's first point of exposure with inhaled e-liquids, is also poorly understood, although evidence is emerging that e-cigarette use is not as safe as previously thought (Eltorai et al. 2019; Gotts et al. 2019) and is associated with increased rates of pulmonary disease (Bhatta & Glantz, 2020). In this review, we shall discuss the effects of e-cigarette-delivered nicotine on the brain and lungs, in an attempt to better understand how nicotine can contribute to the altered physiology seen with e-cigarette exposure.

E-cigarettes as an alternative to smoking tobacco

The effects of e-cigarettes are not well understood and represent a poorly characterized health risk (Dinakar & O'Connor, 2016; Gotts et al. 2019). E-cigarettes are widely perceived as a safer alternative to tobacco smoking (Gravely et al. 2014; McMillen et al. 2015; Filippidis et al. 2017). However, public health specialists have offered differing opinions regarding their safety and there are conflicting data regarding their usefulness as smoking cessation tools (Hartmann-Boyce et al. 2016; Jankowski et al. 2017). Public Health England recently doubled down on previous advice that e-cigarettes are 95% safer than smoking and that people should switch from tobacco to e-cigarettes (East et al. 2018). This advice was based on a panel review that estimated that the risk of vaping is <5% that of smoking based on the number of known cancer-causing agents (Nutt et al. 2014). This advice has recently been questioned (Eissenberg et al. 2020) and a recent European Respiratory Society task force noted that the long-term health effects of vaping are unknown and there is no evidence that e-cigarettes are safer than tobacco (Bals et al. 2019). In multiple countries, the popularity of e-cigarettes amongst youths has led to increased nicotine use, whilst tobacco smoking rates amongst similar age groups is flat or declining (Cullen et al. 2018; Hammond et al. 2019), and there is also concern that e-cigarette-mediated nicotine adoption by youths may lead to long-term nicotine dependency.

Nicotine overview

Nicotine is an alkaloid that is secreted from plants of the nightshade family as an insecticide. Nicotine binds to nicotinic acetylcholine receptors (nAChRs), ubiquitously expressed ligand-gated cation channels that are related to GABA and 5-HT receptors (Albuquerque et al. 2009; Benowitz, 2009). They are composed of five subunits and each subunit has four transmembrane domains and an extracellular N-terminal ligand binding site (Fasoli & Gotti, 2015). They are classified as either α or β based on the presence or absence of an extracellular cysteine domain, respectively, and there are eight human α-subunits (α2–7, 9, 10) and three β-subunits (β2–4) (Dani, 2015). Combinations of these subunits produce numerous nAChRs with variable ligand binding affinities and physiological roles (Dani, 2015). Acetylcholine is the physiological ligand for these receptors, and binding of acetylcholine or exogenous nicotine opens the channel to allow influx of cations (Na⁺, K⁺ and Ca²⁺). The channels subsequently close and become desensitized (Dani, 2015). The reinforcing effects of nicotine are primarily mediated by the α7 and α4β2 nicotinic receptors in the mesolimbic reward pathway, whilst α7 receptors are commonly expressed in the lung and in immune cells (Gahring & Rogers, 2006; Zdanowski et al. 2015). nAChR activation causes excitation of neighbouring neurons, resulting in rapid synaptic transmission (Fasoli & Gotti, 2015). However, these neuronal excitatory effects are downregulated by chronic exposure to low concentrations of nicotine (Dani, 2015). nAChRs (α4β2) rapidly desensitize upon nicotine binding, and upregulation/resensitization leads to nicotine craving (Rose, 2007; Benowitz, 2010; England et al. 2015). Whilst nicotine has been studied on its own, its contribution towards tobacco-induced lung pathology is less well understood, since it tends to be studied along with the other chemicals in cigarette smoke rather than in isolation. It is tacitly assumed that free base nicotine will behave similarly when added directly, in an e-cigarette aerosol or in tobacco smoke. However, there is a knowledge gap in the field and this relationship has not been extensively tested. Moreover, Juul-type e-liquids contain nicotine salt, rather than nicotine free base, and its effects on the airways, brain and other organs, as well as its efficacy relative to freebase nicotine, are poorly understood.

Connecting nicotine, the lung and the brain

Addiction to nicotine drives the repeated exposure to electronic nicotine vapor in humans (Fig. 1). Indeed, exposure to nicotine is reinforcing and can lead to repeated cycles of intake culminating in the need for regular consumption and withdrawal symptoms during periods of abstinence (Markou, 2008). One of the primary goals of addiction research is to understand how nicotine or other drugs of abuse augment or impair cellular functions to produce long-lasting maladaptive changes to brain circuitry that promote addiction. However, nicotine passes through the lungs and cardiovascular system before it reaches the brain. Thus, it is important to understand the detrimental effects of nicotine from a systems perspective. The rest of the body, and the lungs in particular, is chronically exposed to nicotine, which leads to activation of peripheral nAChR. Thus, future studies will need to examine the interplay between peripheral and central effects of nicotine: for example, (1) how nicotine can directly alter cell signalling pathways both centrally and peripherally to change gene/protein expression, and (2) how peripheral alterations can trigger maladaptive changes in specific regions of the lungs and brain.

Figure 1. Nicotine intake alters lung homeostasis and acts in the brain to promote addiction

_{(1) Nicotine is inhaled into the lungs where it equals or exceeds 50 μm in the airway surface liquid. (2) Nicotine can activate nAChRs in the lung. (2a) Nicotine may inhibit the CFTR Cl− channel, potentially leading to dehydration. (2b) Nicotine stimulates protease release from immune cells, which may lead to (3) lung damage (e.g. bronchiectasis and emphysema). (4) Nicotine is absorbed systemically where it then crosses the blood–brain barrier. (5) Nicotine acts on the reward centres in the brain (ventral tegmental area, VTA; nucleus accumbens, NAc) to release dopamine. (6) nAChR densensitization and subsequent upregulation promotes (7) neuroplastic changes associated with craving leading to repeated nicotine uptake and more exposure into the lungs (1).}

The effects of nicotine on neuronal adaptations and behaviour

The behaviours associated with nicotine exposure and dependence are mediated by cellular adaptations as the brain responds to repeated cycles of exposure and withdrawal. With prolonged use, these central adaptations can lead to near-permanent changes in neurons and neuronal networks (Markou, 2008). A number of brain regions have been identified as targets of nicotine-induced plasticity, including the amygdala and the mesolimbic reward pathway (Adinoff, 2004). The mesolimbic reward pathway originates in the ventral tegmental area (VTA) with dopamine projections into the nucleus accumbens. Nicotine, as well as drugs like cocaine, amphetamine and alcohol, increases mesolimbic dopamine signalling by enhancing the excitability of VTA dopamine cells. Nicotine acts at nAChRs expressed in VTA dopamine neurons as well as on local GABAergic interneurons and afferent terminals (Pidoplichko et al. 2004) to alter dopamine neuron excitability through direct actions on dopamine cell bodies as well as alterations in local GABAergic and glutamatergic transmission (Mansvelder & McGehee, 2000, 2002; Mansvelder et al. 2002). Nicotine-induced augmentation of mesolimbic dopamine signalling is particularly sensitive to mechanisms regulating the excitability of VTA dopamine cell bodies (Pidoplichko et al. 2004). Substantial evidence indicates that the motivational effects of nicotine are largely mediated through the VTA. For example, lesions of VTA dopamine neurons or intra-VTA infusion of nAChR antagonists decreases nicotine self-administration (Corrigall et al. 1992, 1994), and mice and rats will self-administer nicotine directly into the VTA in a manner sensitive to nicotinic acetylcholine and dopamine receptor blockade (Ikemoto et al. 2006). These studies indicate that motivational and rewarding effects of nicotine are mediated by increased excitation of VTA dopamine cells (Mansvelder & McGehee, 2000, 2002; Mansvelder et al. 2002). In contrast to acute exposure, chronic nicotine is associated with a diminished dopaminergic state. VTA dopamine cell firing (Liu & Jin, 2004), tonic and phasic dopamine release and extracellular dopamine levels in striatal regions of rodents and non-human primates (Takahashi et al. 1998; Rahman et al. 2004; Domino & Tsukada; Zhang et al. 2012), and dopamine metabolite levels in cerebrospinal fluid from human smokers (Geracioti et al. 1999) are all decreased following chronic nicotine exposure. These deficits in dopamine transmission are thought to contribute to decreased brain reward function (Epping-Jordan et al. 1998) and nicotine withdrawal symptoms including depressed mood, decreased arousal and sleep disturbances (Takahashi et al. 1998; Rahman et al. 2004; Domino & Tsukada, 2009; Zhang et al. 2012). Chronic exposure-related deficits in dopamine function partially result from nicotine-induced disruptions in excitatory and inhibitory mechanisms regulating midbrain dopamine cell activity (Takahashi et al. 1998; Rahman et al. 2004; Domino & Tsukada, 2009; Zhang et al. 2012). In addition to effects on the central nervous system, nicotine has significant effects on the parasympathetic nervous system, including increased locomotion and decreased body temperature (Javadi-Paydar et al. 2019). Thus, irrespective of its source, inhaled nicotine produces significant cellular neuronal adaptations.

Nicotine pharmacodynamics

After e-cigarette inhalation, blood nicotine levels typically peak at ∼120 nm (St Helen et al. 2016). In contrast, little has been done to study nicotine levels in the lung. Unlike for blood and urine, measuring nicotine levels in the lung is a technically challenging endeavour that requires sampling of the airway surface liquid (ASL) that lines the lung lumen either by performing bronchoscopy and obtaining bronchoalveolar lavage or by obtaining sputum. Further, the nature of these techniques makes repeat measurements difficult, so it is harder to develop comprehensive lung nicotine pharmacodynamic profiles. This impediment notwithstanding, we have previously measured nicotine levels in sputum of smokers and vapers (Clunes et al. 2008; Ghosh et al. 2019). Here, we corrected for any dilution factors by measuring levels of lung urea, since this biomarker is typically at equilibrium between blood and sputum. Using this approach, we found that sputum nicotine levels were ∼30 μm for smokers (Clunes et al. 2008). We found that sputum nicotine levels in vapers were ∼50 μm (Ghosh et al. 2019). Moreover, since these measurements were made ∼30 min after vaping, we may be markedly underestimating the amount of nicotine seen by the lung, since nicotine is likely transepithelially absorbed in an exponential fashion. E-liquids contain between 3 and 18 mg ml⁻¹ of nicotine, which equates to between ∼18 and 112 mm. Thus, if we are seeing ∼50 μm nicotine after ∼30 min, the initial nicotine concentration seen by the lung is likely much higher and possibly in the millimolar range. Clearly, more studies are needed to fully determine the impact of e-cigarette device type and e-liquid type (including nicotine concentration), as well as variations in subject topography on lung nicotine levels.

The effects of nicotine on the lung

Airway epithelia

Airway epithelia line the lung lumen (Whitsett & Alenghat, 2015). They help modulate ASL volume/composition, secrete mucins, secrete cytokines that can trigger leukocyte infiltration and also form a barrier against invading pathogens (Shaykhiev & Crystal, 2013). Airway epithelia are deranged following chronic tobacco smoke exposure and undergo significant changes in gene and protein expression that lead to a loss of barrier function, goblet cell metaplasia and altered inflammatory status (Ghosh et al. 2015; Strzelak et al. 2018). We have found that vaping causes significant changes to the airway epithelial proteome that are distinct from the changes seen in smokers. These changes were accompanied by an altered physical appearance of the airways, and vapers’ airways had a distinct reddish colour that was indicative of erythema and increased friability (Ghosh et al. 2018). However, further studies will be required to determine the impact of nicotine on these changes. The effects of vaping on the lungs of never-smokers have been studied. Never smokers inhaled a nicotine-containing e-liquid and saw significant changes in gene expression (Staudt et al. 2018). In a second study, in which subjects only inhaled propylene glycol/vegetable glycerine, the changes appeared to be much smaller (Song et al. 2020), suggesting that changes may have been nicotine-dependent. Thus, inhaling nicotine via e-cigarettes may contribute to the changes seen in vapers’ airways.

ASL provides an appropriate environment for immune cell function and is a source of proteases and protease inhibitors (Hiemstra, 2015; Taggart et al. 2017). Maintenance of ASL hydration is critical for efficiently clearing mucus out of the lungs. Indeed, in both cystic fibrosis and chronic obstructive pulmonary disease (COPD), dysfunctional cystic fibrosis transmembrane conductance regulator (CFTR)-mediated anion secretion contributes to ASL dehydration that leads to mucus plugging, chronic infection and inflammation, and lung damage (i.e. bronchiectasis) (Collawn & Matalon, 2014; Ghosh et al. 2015). In COPD airways, mucus dehydration inversely correlates with a decline in lung function and also is a predictor of mortality (Hogg et al. 2004; Anderson et al. 2015). More recently, nicotine has been shown to inhibit CFTR function leading to decreased Cl⁻ secretion, decreased ciliary beating and decreased airway hydration (Fig. 1; Garcia-Arcos et al. 2016; Chung et al. 2019; Lin et al. 2019). Whilst the mechanism of nicotine-dependent CFTR inhibition is not fully understood, we have previously found that CFTR is inhibited by elevations in cytoplasmic Ca²⁺ (Rasmussen et al. 2014; Patel et al. 2019). This causes CFTR dephosphorylation (Marklew et al. 2019), and we speculate that nicotine-dependent Ca²⁺ influx through nAChRs likely inhibits CFTR through a similar process, indicating a mechanistic link between nicotine intake and epithelial ion channel dysfunction.

Pulmonary immune cells

Alveolar macrophages are resident innate immune cells that phagocytose, and secrete cytokines, chemokines and growth factors (Gordon & Read, 2002; Rubins, 2003; Phipps et al. 2010; Lawal, 2018). nAChRs are highly expressed in pulmonary immune cells (Gahring & Rogers, 2006). For example, α7 nAChR knockout mice show a blunted pulmonary response to cigarette smoke exposure (Gahring et al. 2017). Alveolar macrophages exhibit functional heterogeneity/plasticity (Gordon & Taylor, 2005; Hao et al. 2012). Notably, long-term activation of macrophages without resolution of inflammation can cause airway damage. Conversely, downregulation of macrophage function can lead to immunosuppression, airway infection and inflammation-associated damage (Simonin-Le Jeune et al. 2013). In the healthy lung, alveolar macrophages make up >90% of the resident immune cells. However, some neutrophils (∼3–5% of the total cell count) are also present, and this number can change drastically during infection and/or inflammation. For example, in COPD lungs, neutrophils become the predominant cell type in the lung (Jasper et al. 2019). Scott et al. (2018) found that e-liquid condensate exposure increased apoptosis and necrosis in alveolar macrophages, in a nicotine-dependent fashion. Similarly, phagocytosis was impaired by nicotine-containing e-liquids, suggesting that innate defence in alveolar macrophages may be impaired. Neutrophils can also phagocytose and release cytokines/chemokines. However, neutrophils are also prone to lysis and can release their intracellular contents, including proteases and DNA into the lung, which can contribute to lung damage and increased mucus/sputum viscosity, respectively (Kaplan & Radic, 2012). Neutrophil lysis and the formation of DNA-containing neutrophil extracellular traps (NETs) is triggered by elevations in extracellular Ca²⁺. Nicotine activation of nAChRs, via its ability to elevate cytoplasmic Ca²⁺, can also induce NETosis/neutrophil lysis (Lee et al. 2017).

Proteases including neutrophil elastase, which as its name suggests, is derived from neutrophils, and macrophage-derived matrix metalloproteases (MMP-2 and MMP-9) are normally expressed in the lung, where they are involved in tissue repair and regeneration (Greene & McElvaney, 2009). However, when chronically upregulated, these proteases cause lung damage (emphysema and bronchiectasis; Fig. 1; Nadel, 2000; Skrzydlewska et al. 2005; Abboud & Vimalanathan, 2008; Fischer et al. 2011). They can also degrade antimicrobial proteins (Webster et al. 2018) and cleave epidermal growth factor receptor leading to altered cellular communication and increased mucin expression (Greene & McElvaney, 2009). We have previously conducted research bronchoscopies on healthy vapers and smokers. We found that neutrophil elastase and macrophage-derived matrix metalloproteases (MMP-2 and MMP-9) were significantly elevated in vapers’ lungs, to the same extent as seen in smokers (Ghosh et al. 2019). Studies of freshly isolated alveolar macrophages and peripheral blood neutrophils from healthy non-smokers revealed that nicotine caused a dose-dependent increase in cytosolic Ca²⁺ and protease release from both cell types (Ghosh et al. 2019). Macrophages were found to be more sensitive to nicotine than neutrophils and their EC₅₀ for protease release was ∼40 nm, which was below the amount of nicotine (∼50 μm) measured in vapers’ sputum. In keeping with these findings, lung protease levels were also elevated in vapers who were never-smokers. In mice, vaping with nicotine and propylene glycol–vegetable glycerine also caused emphysema (Garcia-Arcos et al. 2016). Given the firmly established link between proteases and lung damage, the potential risk to vapers’ lungs from nicotine-induced proteolysis cannot be overstated.

Future studies and conclusions

To improve understanding of the impact of e-cigarette/nicotine exposure on the lung and brain, greater integration between clinical researchers and behaviourists studying human e-cigarette-mediated nicotine intake and laboratory researchers studying animal and cellular models of e-cigarette/nicotine exposure is required. One future challenge will be to accurately reproduce human nicotine intake and exposure levels in the laboratory. Moreover, exposure levels will likely differ depending on the organ system being studied, with higher levels of exposure seen in the lungs than in the brain or other systems. Differentiating the peripheral and central effects of nicotine, and how these distinct but parallel processes interact, potentially through inflammatory signalling or neuroimmune activation, is also an important area of future study.

Animal models will be essential in studying the effects of vaping. To date, mice have been exposed to e-cigarette vapour, leading to emphysema, increases in mucin levels and lipid accumulation, amongst other findings (Garcia-Arcos et al. 2016; Ghosh et al. 2018; Madison et al. 2019). However, other animals including large animals whose airways more accurately reflect human airway physiology will be important. For example, sheep have also been exposed to e-cigarette vapour, which causes mucus stasis (Chung et al. 2019). Importantly, animal models will allow for the study of multi-organ pathology. For example, vaping impairs embryo implantation in pregnant mice and alters the development of the offspring (Wetendorf et al. 2019). Vaping also induced fibrosis and caused impaired renal function in mice (Crotty Alexander et al. 2018). Regardless of the animal type or organ studied, challenges facing the field include (1) possible strain-dependent effects, (2) lack of appropriate e-cigarette aerosol exposure regimens, and (3) given the large number of e-liquids that are commercially available (over 7000 and counting) and the dynamic nature of the market place, finding an appropriate e-liquid to use. For example, whilst Garcia-Arcos et al. (2016) found emphysema after vaping mice, Madison et al. (2019) did not, and instead found altered lipid accumulation, which may have been due to strain dependencies or different vape exposure protocols. Similarly, Lee et al. (2018) exposed mice to e-cigarette aerosol for a year, which is a massive time commitment, and during this time, vendors may change the composition of, or discontinue e-liquids. This field is still in its infancy, and standard test e-liquids and standard exposure protocols are urgently needed, much akin to the Kentucky research cigarettes and standard exposure protocols used with conventional cigarettes.

In conclusion, electronic vaporization of nicotine likely promotes the same addictive behaviours as nicotine exposure through conventional means, resulting in increased chronic/repeated use, which will have deleterious effects in the brain and lung (Fig. 1). The lung has evolved to be highly resilient and it typically takes decades of tobacco smoke exposure before pathology emerges (i.e. COPD or lung cancer). Thus, even though e-cigarettes have already been shown to induce changes to multiple regions of the lung (Gotts et al. 2019), what we are seeing is likely to be only the tip of the iceberg. Indeed, whilst incidences of lung cancer and COPD spiked to match peak tobacco smoking usage in the last century and are now falling, there was a lag time between the two events, with tobacco use declining before disease. Decades from now, we may see a new e-cigarette-dependent spike in lung disease, so it is critical that addiction researchers and those studying the lung and other systems exposed to nicotine work together on this problem in order to avoid a late 21st century nicotine/e-cigarette addiction and lung disease epidemic.

Summary

Electronic cigarettes deliver nicotine via a heated aerosol, posing a significant public health challenge due to their increasing popularity and unclear long-term health effects. While often perceived as a safer alternative to traditional smoking, evidence suggests that e-cigarettes are not harmless and may contribute to various physiological changes in both the brain and the lungs. Research is urgently needed to clarify the extent of these effects and inform appropriate public health strategies.

E-cigarettes as an Alternative to Smoking Tobacco

The comparative safety of e-cigarettes versus traditional cigarettes remains a subject of considerable debate within the scientific and public health communities. While some organizations promote e-cigarettes as a less harmful alternative for smokers, contradictory data exist regarding their efficacy as cessation aids and their overall health implications. The long-term health consequences of vaping remain largely unknown, prompting ongoing investigation and cautionary pronouncements from prominent health organizations. The rise in e-cigarette use among youth further exacerbates concerns about nicotine addiction and potential long-term health risks.

Nicotine Overview

Nicotine, a potent alkaloid, exerts its effects through the activation of nicotinic acetylcholine receptors (nAChRs). These receptors, distributed throughout the body including the brain and lungs, are ligand-gated ion channels with diverse subunit compositions influencing their functional properties. Nicotine's rewarding effects are primarily attributed to its actions on specific nAChR subtypes in the mesolimbic reward pathway. However, chronic nicotine exposure leads to receptor desensitization and subsequent upregulation, contributing to nicotine dependence and withdrawal symptoms. The precise effects of nicotine, whether delivered via e-cigarettes or other means, and especially in combination with other e-liquid components, require further investigation.

Connecting Nicotine, the Lung, and the Brain

Nicotine's systemic effects necessitate a holistic perspective encompassing both its impact on the brain and the lungs. The lungs, the initial point of contact, experience direct nicotine exposure leading to potential airway damage, while the subsequent systemic absorption of nicotine triggers rewarding effects in the brain, further perpetuating addiction. Future studies must explore the intricate interplay between peripheral and central nicotine actions, considering their synergistic influence on gene/protein expression and potential maladaptive changes in lung and brain physiology.

The Effects of Nicotine on Neuronal Adaptations and Behavior

Nicotine's impact on behavior and dependence arises from cellular adaptations within the brain. Chronic nicotine use induces neuroplasticity in brain regions, including the amygdala and mesolimbic reward pathway, affecting dopamine signaling. While acute exposure enhances dopamine release, chronic exposure results in diminished dopaminergic activity, contributing to reward deficits and withdrawal symptoms. Understanding the intricate mechanisms of these adaptations is crucial for developing effective strategies to mitigate nicotine addiction.

Nicotine Pharmacodynamics

Determining nicotine levels within the lung presents considerable analytical challenges. While blood nicotine levels following e-cigarette use are relatively well characterized, lung nicotine concentrations are less understood due to the difficulties in accurately sampling airway surface liquid. Preliminary data suggest that lung nicotine levels in vapers are substantially higher than in blood, potentially exceeding millimolar range, highlighting the need for further research to fully characterize lung nicotine exposure.

The Effects of Nicotine on the Lung

Airway epithelia, crucial for maintaining lung homeostasis, exhibit significant alterations following chronic nicotine exposure. E-cigarette use induces changes in airway epithelial proteomes, potentially compromising barrier function and inducing inflammation. Nicotine's inhibition of CFTR-mediated anion secretion contributes to airway dehydration and mucus accumulation. Furthermore, nicotine increases protease release from pulmonary immune cells, inducing cellular damage, which may exacerbate lung damage. In conclusion, studies clearly indicate nicotine's deleterious effects on lung health.

Future Studies and Conclusions

Future research requires a multidisciplinary approach integrating human observational studies with laboratory investigations using both animal and cellular models. Standardizing e-cigarette exposure protocols and accounting for variations in e-liquid compositions are crucial steps for producing robust and reliable data. Exploring the interplay between peripheral and central effects of nicotine and its consequences for various organ systems will be vital in determining the long-term health effects of e-cigarette use. The current evidence highlights the potential for a future increase in lung diseases due to e-cigarette use, indicating the pressing need for comprehensive, coordinated research efforts.

Summary

E-cigarettes deliver nicotine via a heated liquid, posing a significant public health challenge due to their increasing popularity and unclear health consequences. While often perceived as safer than traditional cigarettes, evidence suggests e-cigarette use is associated with pulmonary issues and may not be an effective smoking cessation tool. The long-term effects on both the brain and lungs remain largely unknown, necessitating further research.

E-cigarettes as an Alternative to Smoking Tobacco

The health risks associated with e-cigarettes are not fully understood, leading to conflicting opinions on their safety and efficacy as smoking cessation aids. Public health guidance varies internationally, with some advocating e-cigarettes as a harm reduction strategy while others highlight the lack of long-term safety data. The rising popularity of e-cigarettes among youth raises concerns about nicotine addiction and its potential long-term health implications, especially considering that tobacco smoking rates are either stable or decreasing within these same populations.

Nicotine Overview

Nicotine, a potent alkaloid, acts on nicotinic acetylcholine receptors (nAChRs) throughout the body. These receptors, ligand-gated ion channels, exhibit diverse subunit combinations resulting in varied physiological roles. Nicotine's reinforcing effects primarily involve α7 and α4β2 nAChRs within the mesolimbic reward pathway. Chronic nicotine exposure leads to receptor desensitization and subsequent upregulation, contributing to nicotine craving and dependence. While nicotine's effects on the brain are well-studied, its role in tobacco-induced lung pathology requires further investigation, especially considering the use of nicotine salts in many e-cigarettes, which differ from freebase nicotine.

Connecting Nicotine, the Lung, and the Brain

Nicotine's addictive properties drive repeated e-cigarette use. Understanding how nicotine impacts cellular function and alters brain circuitry to promote addiction is critical. Since nicotine travels through the lungs and cardiovascular system before reaching the brain, a systems-based approach is necessary to assess its detrimental effects. Future research should investigate the interplay between peripheral and central nicotine effects, considering how they influence gene expression and contribute to maladaptive changes in the lungs and brain.

The Effects of Nicotine on Neuronal Adaptations and Behavior

Nicotine exposure and dependence cause significant cellular adaptations within the brain, leading to lasting changes in neuronal structure and function. The amygdala and mesolimbic reward pathway are primary targets, with nicotine impacting dopamine signaling. Acute exposure increases dopamine release, while chronic exposure leads to decreased dopamine function, potentially contributing to withdrawal symptoms. Beyond central nervous system effects, nicotine also impacts the peripheral nervous system, causing changes in locomotion and body temperature.

Nicotine Pharmacodynamics

While blood nicotine levels after e-cigarette use are relatively well-characterized, lung nicotine levels remain poorly understood due to challenges in sampling airway surface liquid (ASL). Studies using sputum analysis suggest significantly higher nicotine concentrations in the lungs compared to blood, possibly in the millimolar range. Further research is needed to fully understand the impact of e-cigarette device and e-liquid variations on lung nicotine levels.

The Effects of Nicotine on the Lung

Airway epithelia, which line the lungs, play a crucial role in maintaining lung homeostasis. E-cigarette use causes alterations in airway epithelial structure and function. Nicotine's inhibition of CFTR, a crucial ion channel, can lead to ASL dehydration, hindering mucus clearance and increasing the risk of lung damage. Pulmonary immune cells, such as alveolar macrophages and neutrophils, also express nAChRs, and nicotine exposure affects their function, potentially contributing to lung inflammation and damage through mechanisms including increased protease release and NETosis. The impact of nicotine-induced protease upregulation on lung tissue damage cannot be overstated.

Future Studies and Conclusions

Collaborative research integrating clinical and laboratory studies is essential to advance understanding of e-cigarette/nicotine effects. Animal models are crucial for studying multi-organ pathology, but challenges remain in replicating human exposure levels and accounting for e-liquid variability. The development of standardized e-liquids and exposure protocols is critical for future research. The long-term consequences of e-cigarette use on lung health are likely significant, highlighting the need for continued research and preventative measures to mitigate potential public health risks.

Summary

E-cigarettes deliver nicotine, a highly addictive substance, via a vaporized liquid. While often marketed as a safer alternative to traditional cigarettes, the long-term health effects of e-cigarettes remain uncertain. Current research suggests that vaping is not harmless and may cause lung damage and other health problems. This is due in part to the high nicotine concentrations found in e-cigarette liquids and the resulting effects on both the brain and the lungs.

E-cigarettes as an alternative to smoking tobacco

The health risks associated with e-cigarettes are still being researched and aren't fully understood. While many believe vaping is safer than smoking, public health experts disagree, with some evidence suggesting it may not be a viable smoking cessation tool. Despite this, e-cigarettes are gaining popularity globally, especially among young people, which has led to increased nicotine use among youth and concerns about long-term addiction.

Nicotine overview

Nicotine is a potent stimulant that works by activating nicotinic acetylcholine receptors (nAChRs) in the brain and body. These receptors trigger the release of dopamine, leading to feelings of pleasure and reinforcement. While the brain's reward system is primarily targeted, nicotine also impacts the lungs directly causing potential harm. The nicotine form used (freebase versus salt) can also influence the effects.

Connecting nicotine, the lung and the brain

Nicotine's addictive nature leads to repeated vaping, impacting both the lungs and the brain. The lungs are the first point of contact, where nicotine can trigger inflammation and damage. This is followed by systemic absorption and the effect on the brain's reward system, which reinforces the addiction cycle. Further research is needed to investigate the interplay between these effects.

The effects of nicotine on neuronal adaptations and behaviour

Nicotine's impact on the brain causes adaptations that lead to addiction. The mesolimbic reward pathway, crucial for pleasure and motivation, is a primary target. Acute exposure increases dopamine release, while chronic use can lead to decreased dopamine levels, causing withdrawal symptoms and reinforcing the addictive cycle. This affects both the central and peripheral nervous systems.

Nicotine pharmacodynamics

E-cigarette vaping delivers high nicotine levels to the lungs, far exceeding those in blood. Measuring lung nicotine levels is difficult, but studies show significantly high concentrations, suggesting a much larger impact on lung tissue than previously thought. More research is needed to understand variations based on devices, e-liquids, and individual factors.

The effects of nicotine on the lung

Nicotine affects the airway epithelia, responsible for lung function and defense, causing changes that can weaken lung defenses and lead to inflammation. Nicotine also disrupts the normal function of the cilia and the airway surface liquid. This contributes to decreased mucus clearance and increased susceptibility to infection. Nicotine's interaction with immune cells in the lungs, like alveolar macrophages and neutrophils, also exacerbates lung damage by increasing the release of proteases, enzymes that break down lung tissue.

Future studies and conclusions

More collaborative research is needed to fully understand e-cigarette impacts. Animal models, using multiple species to better simulate human responses, will be crucial, along with more standardized testing methods for e-liquids. The long-term effects on the lungs, similar to those seen with traditional cigarettes, are still unknown but are of significant concern. The potential for a future e-cigarette-related lung disease epidemic underscores the urgency for further research and public health intervention.

Summary

E-cigarettes are like fancy vaporizers that heat up liquid with nicotine and flavors. People use them to get nicotine into their brains, just like with regular cigarettes. But unlike regular cigarettes, vaping isn't as strictly controlled, and lots of people are using them. Scientists are still figuring out if e-cigarettes are safer than regular cigarettes; there's a lot of debate, and some studies show vaping isn't as harmless as some people think. This article discusses how nicotine from e-cigarettes affects the brain and lungs.

E-cigarettes and Smoking

Scientists aren't entirely sure what e-cigarettes do to your body. Many people think they're safer than regular cigarettes, but experts disagree. Some say e-cigarettes are much safer, while others say we don't know enough yet. A lot of kids are vaping, even though smoking rates are going down. This worries people because nicotine can be addictive.

Nicotine

Nicotine is a special ingredient found in some plants. It works by attaching to special spots in your body's cells, called receptors. These receptors are everywhere, even in your brain and lungs. Nicotine makes your brain release dopamine, which feels good. But using nicotine a lot can change how your brain works, making it hard to stop using it.

Nicotine's Effects on the Body

Nicotine first goes to your lungs and then to your brain. It can harm your lungs and also makes your brain want more nicotine, leading to addiction. Scientists are working to understand how these effects happen.

Nicotine and the Brain

Nicotine changes the way your brain works. It can make you feel good at first, but using it too much can change your brain cells and make it harder to stop. This leads to things like cravings and withdrawal symptoms.

How Much Nicotine is in E-Cigarettes?

It’s hard to measure exactly how much nicotine your lungs get when you vape, but studies suggest it's a lot. E-cigarette liquid can have different amounts of nicotine, which makes it hard to study. More studies are needed to know for sure.

Nicotine's Effects on the Lungs

Nicotine can damage your lungs' lining. This lining protects your lungs and helps you breathe. Nicotine can also cause problems with how your lungs clean themselves, and even make your lungs more likely to get sick.

More Research Needed

Scientists need to do more studies on vaping, especially how it affects different parts of the body over a long time. They need to use different types of animals and vaping methods to really understand the effects. It's also important to figure out which parts of vaping are most harmful and how to make e-cigarettes safer.

Conclusion

Vaping is likely just as addictive as other forms of nicotine use and has harmful effects on the brain and lungs. Although lung damage from vaping may take a long time to show, it is important to study this now, before widespread damage occurs.