Toxicity from 10 different flavored E-cigarette vapors to the cells that line the lungs

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The flavor on the bottle of E-liquids is no indication of the potentially harmful effects of one compared with another.

Dr. Miranda Ween from the University of Adelaide and South Australia’s Royal Adelaide Hospital led a study, in collaboration with Dr. Laura E. Crotty Alexander at the University of California San Diego, to investigate the lung health risks of E-cigarette vapor from a number of different flavored E-liquids.

“We studied the level of toxicity from 10 different flavored E-cigarette vapors to the cells that line the lungs and how lung immune cells – macrophages – cleared away bacteria from healthy non-smoking donors, replicating the possible harm to non-smokers who use E-cigarettes,” said Dr. Ween.

“Lung cell toxicity and bacterial clearance by macrophages was affected by almost every flavor, but some such as mango and tobacco showed minimal toxicity and immune effects.”

“Banana had moderate effects, and chocolate in particular had an unexpectedly high impact, killing almost all the cells and blocked the ability of macrophages to clear away bacteria almost entirely.”

E-liquid is made up of propylene glycol, vegetable glycerine, and flavorings, and, outside Australia, often sold containing nicotine.

Battery operated E-cigarettes heat the E-liquid to produce an aerosol, commonly known as vapor, that the ‘vaper’ inhales.

They were designed to replace cigarettes and thus deliver aerosol vapor directly to the consumer’s lungs. However, their popularity amongst never-smokers is increasing with 6.9 percent of non-smoking Australians having tried one by 2019.

Ninety percent of E-cigarette products sold globally are made in China. In 2019, the global E-cigarette market was valued at US $12.41 billion and is expected to expand.

“Ninety-nine percent of E-cigarette liquids are flavored. To create these flavor profiles, companies are adding multiple chemicals to achieve that ‘perfect’ taste,” said Laura Crotty Alexander, MD, associate professor of medicine in the Division of Pulmonary, Critical Care and Sleep Medicine at University California San Diego and Section Chief of Pulmonary Critical Care at the VA San Diego Healthcare System.

“These chemicals have been found to be toxic to the lungs. When inhaled, they wreak havoc on the lungs and affect specialized protein levels that help keep the body’s immune system on track.”

With thousands of different flavors ranging from the simple sounding banana and mango to the more ambiguous such as Unicorn Puke and Stoned Smurf, and ingredients not required to be listed on the bottle, it is impossible for users to know what they are inhaling.

“Our study demonstrated to us that the name on the bottle is not what is important, it is what goes into the E-liquids and put into E-cigarettes which matters,” said Dr. Ween.

“The flavoring chemicals included, how many different ones are in the E-liquid, and how much of each goes into an E-liquid can all contribute to how much damage they may be doing to the lungs.”

Further study into a number of chocolate and banana flavored E-liquids made by several companies showed that the toxicity and immune effects were not the same between brands, and mass spectrometry analysis showed that the flavoring chemical compositions and their concentrations were different.

“E-liquids with the highest levels of benzene-rich flavoring chemicals had the greatest toxicity and immune cell dysfunction, whilst those with no or low levels of benzene-rich flavoring chemicals tended to show minimal damage,” said Dr. Ween.

“Both types of cells from the healthy donors also showed abnormal inflammation response markers when exposed to E-cigarette vapor. When vapers were recruited at UC San Diego to investigate this further, their saliva was found to also show an abnormal immune response markers compared with non-vaping/non-smoking controls.”

This study points to vapers having possible difficulties responding to lung infections.

“We hear a lot about banning specific flavors of e-liquids as the way to move forward, but this study shows that the name on the bottle isn’t what needs to be controlled to reduce the risks to vapers, and that allowed flavors need to be well defined,” said Dr. Ween.

“This could easily be achieved by only limiting E-liquids to a single flavoring chemical which has had its effects in the lung tested and safe concentrations determined, instead of banning a particular flavor name.”

“Most importantly, we need major funding for independent research into which flavors represent the lowest levels of risk, something Australia is currently lacking.”


The use of electronic cigarettes (E-Cig) or electronic nicotine delivery systems (ENDS) has reached epidemic levels among young adults in the US. Currently, an estimated 10 million US adults and over three million high school adolescents are active ENDS users (including e-juices and pod based systems) with as high as 27.5% of high school students in 2019 (Cullen et al., 2018; Cullen et al., 2019; Gentzke et al., 2019) and 10.5% of middle school students reported current (past month) ENDS use (Wang et al., 2018). As a result, the FDA Commissioner declared in 2018 that ENDS use among youth reached “nothing short of an epidemic proportion of growth” (Printz, 2018).

ENDS products encompass all the E-Cigs, vapes, e-hookahs, vape pens, tank systems, pods, and mods used at high temperatures. Using ENDS products is commonly referred to as vaping. ENDS products work by heating the e-liquid or e-oil provided in cartridges to produce an aerosol/vapor that users inhale into their lungs.

The e-liquid or e-oil may contain nicotine, tetrahydrocannabinol (THC) and/or cannabinoid (CBD), and other substances and additives (flavors), that has hugely contributed to the popularity of ENDS use.

There are more than 7,000 flavors including fruit or candy essences added to enhance the “experience”.

Effective delivery of nicotine in the form of a vapor utilizes vehicle solvents like propylene glycol (PG) and vegetable glycerin (VG), which are generally regarded safe by the FDA as food additives. Little is known about how ENDS constituents, e.g. PG and VG, affect the respiratory tract and its local immune-inflammatory functions.

Emerging evidence indicates that the acute effects of ENDS or vaping products use on the respiratory system are of particular concern (Khan et al., 2018; Sommerfeld et al., 2018; Viswam et al., 2018; Layden et al., 2019; Madison et al., 2019). To date, all 50 US states have reported “a cluster of mysterious pulmonary illnesses” that may be related to E-Cig use with at least 2,291 potential cases and 48 associated fatalities as of December 3, 2019 (Blagev et al., 2019; Chatam-Stephens et al., 2019; Gentzke et al., 2019; Jatlaoui et al., 2019; Kalininskiy et al., 2019; Taylor et al., 2019).

In addition, there are at least seven published case reports from 2012 to 2018 describing similar conditions in E-Cig users with no identifiable infectious etiology and the differential diagnosis includes acute lung injury, atypical pneumonitis, eosinophilic or lipoid pneumonia, as reviewed in (Khan et al., 2018; Viswam et al., 2018).

Accordingly, CDC has declared an “outbreak” of the e-cigarette or vaping product use associated lung injury or “e-cigarette or vaping product use associated lung injury” (EVALI) throughout the United States (Blount et al., 2019a; Moritz et al., 2019; Navon et al., 2019). Nevertheless, the recent EVALI cases from Canada and Barcelona highlight the importance of understanding the pathogenesis of EVALI and the treatment options available outside the United States (Casanova et al., 2019; Landman et al., 2019). This article provides perspectives of e-cig vaping on chemistry, toxicity, and pathological mechanisms on current episodes of EVALI.

Causes and Symptoms of EVALI
Among EVALI affected subjects where the lung samples were available, abnormal lipid-laden macrophages that are associated with lipoid and other forms of pneumonia were observed. The presenting symptoms include cough, shortness of breath/dyspnea, chest pain, nausea, vomiting/diarrhea, fatigue, fever, and/or weight loss.

The fast development of this clinical entity suggests that some subclinical reactions with unknown long term health implications are taking place in the lungs of most ENDS/THC products’ (including wax and dabs) users, with EVALI cases representing the tip of the iceberg. Indeed, sporadic cases of EVALI had been reported in the UK, EU, and elsewhere, despite highly variable public health policies and also in many places there is no clearly identified reporting system for such cases (Rehan et al., 2018; Biondi-Zoccai et al., 2019).

Pathophysiology of EVALI, and the Presence of Vitamin E Acetate in BALF of EVALI Patients
Most of the subsequent analysis has been geared towards the constituents of E-liquids/E-juice or vaping products like Vitamin-E (alpha-tocopherol) acetate (VEA) which is being implicated as the likely ‘exogenous’ source of lipids in these ENDS-user subjects (Sommerfeld et al., 2018; Viswam et al., 2018; Layden et al., 2019), and perhaps a causal factor because it was detected in the bronchoalveolar lavage fluids (BALF) of several cases with EVALI and ENDS use history (Reidel et al. 2018; Moritz et al., 2019).

For e-liquids, VEA (or vitamin A, retinoic acid) is used as an additive to dissolve/dilute (cutting agent) THC oils along with mineral, coconut oil, and triglyceride medium chain oil, and is also used as a thickening agent for other non-THC e-liquids.

Thus far, in a nationwide study, VEA, coconut oil, and limonene (terpene) have been identified in 94%, 2%, and 3% of EVALI patient BALF samples, respectively (Blount et al., 2019b). The absence of these compounds in healthy comparators makes VEA the potential causative agent for EVALI. VEA is not harmful when ingested and is found in many foods but when inhaled it can have a protective role against oxidative stress and inflammatory responses (Hybertson et al., 1998; Wang et al., 2002; Hybertson et al., 2005).

Further, it acts as a carrier for drug delivery (Shukla et al., 2014), suggesting it may serve as a carrier for THC in the blood and brain of users. It may be possible that when inhaled/vaporized, VEA or its oxidant/radical derivatives may interfere with physiological lung functions by interacting with phospholipids and surfactants of the epithelial lining fluid (Xue et al., 2005; Beattie and Schock, 2009).

There is an urgent need for evidence-based studies to assess the role of VEA in the development of EVALI or other ENDS-associated lung conditions. In addition, inhalation toxicology and aerosolization chemical studies are needed to investigate all the other constituents of the e-liquids or the cartridges used by the users/patients.

Discussion on Toxicity and Biomarkers of EVALI
Recent histopathological reports showed the presence of burnt/blackened lungs, suggesting that aromatic/volatile hydrocarbons, including terpenes (diluent) and oils, are involved in EVALI (Butt et al., 2019; Triantafyllou et al., 2019). There are five components that affect the toxicity of these agents: cutting agents or oils, temperature, flavoring (e.g. vanillin, menthol, camphene, myrcene, pinene, and lemon-limonene), additives, and heavy metals (lead, arsenic, nickel, mercury) based on counterfeit/bootleg cartridges versus legal or medical cartridges. PG/VG, VEA, and medium-chain triglycerides (MCT oil) and mineral oil along with terpenes (camphene, myrcene, pinenes or limonenes used to attract users) are used to dilute THC wax/oil (known as dabs), as well as nicotine in commercial ENDS liquids. Various hydrocarbons (acrolein, 1,3, butadiene, benzene, toluene, and propene) and reactive aldehydes are formed upon heating these compounds to around 500°F.

All these cartridges, including CBD containing cartridges are used at around the common voltages (e.g. 3.5 V to 5.5 V) using a specific device. It is also believed that the counterfeit products used cartridges that contained pesticides or pesticides (e.g. myclobutanil) came from extraction of THC oil. It is likely that these products will generate varying degree of particles and particulate matter in microns, and deposit on different sites in the lung.

In contrast to the e-liquid constituents, the lipid derivatives from the ‘endogenous’ source such as the epithelial lining fluid (ELF) and/or lung surfactants and their constituents, i.e. phospholipids, including dipalmitoylphosphatidylcholine (DPPC), could also be associated with the inflammatory responses of innate immune cells of ENDS users. Hence, the airway lipid dysregulation might also be contributing to the ENDS use associated inflammatory responses and perhaps is involved in EVALI as well.

Therefore, the rapid and mass spread of ENDS among US young adults, and the seriousness of potentially acute lung reactions (including fatality), calls for a systematic investigation of ENDS use inflammatory responses (Perrine et al., 2019). This would not only culminate in EVALI, but also develop other comorbid conditions involving cardiomyopathies. This problem may be more augmented in those states where recreational THC products are currently banned, where the marketing (street sellers) may be more obvious than in those states where it is acceptable to sell.

Besides the source of the lipid dysregulation, there is an urgent need to establish the biomarkers that correlate with the acute response to ENDS use or EVALI as recommended by recent CDC guidelines (Blount et al., 2019a; Navon et al., 2019). The recent emergence of system biological approaches, such as genomic, epigenetic, metabolomic, lipidomic, proteomic, and transcriptomic, or in combination as a multi-omic approach has shown some promising biomarkers in acute lung injury etiology (Li et al., 2018), and may help in understanding the susceptibility and causative mechanisms of EVALI among ENDS/vaping product including pod/mod users.

Nonetheless, substantial research efforts are needed to define better biomarkers in various biological fluids, e.g. plasma/serum, exhaled breath condensate, EBC, and sputum to help diagnose and treat the complex pathophysiology of EVALI (Singh et al., 2019)- ERJ Open.

E-cigarettes are highly heterogeneous (with various grades of severity) and evolving in design with different e-liquids with different nicotine levels (including nicotine-free), benzoic acid/benzoate, nicotine salts, and flavoring agents contribute to the variability across e-cigarette products.

And the most recent, “fourth generation” ENDS use was reportedly shown to induce transient lung inflammation and gas exchange dysregulation (Chaumont et al., 2019). Though EVALI is significantly involved in subjects vaping adulterated/counterfeit cartridges, the role of those cartridges which are legally available in legalized states cannot be ruled out.

Disussion on Cellular and Molecular Mechanisms of EVALI
Certain mechanistic approaches can be presented to understand the mechanisms of EVALI. These biochemical, cellular, and molecular changes are known to occur by e-cig vaping. The following sections provide some of the interesting current hallmarks on the observed mechanisms of lung injuries caused by ENDS use.

Several physiologic mechanisms, including lung surfactants, mucociliary clearance, and phagocytosis of the inhaled particulates, are paramount in maintaining the airway homeostasis. The airway epithelial cells (AECs), including alveolar type I (AT-I) and type II (AT-II) cells, alveolar macrophages (AMs), and the granulocytes or polymorphonuclear cells (PMNs) are the prominent airway innate immune cells driving these physiological functions and are among the first responders following the ENDS aerosol/vape exposure, as depicted in Figure 1 AMs are the resident professional phagocytes that ingest and degrade different inhaled irritants, pathogens, and apoptotic cells by ‘‘efferocytosis’’ to help reduce inflammatory responses in the damaged tissues (Ween et al., 2019).

Exposure to ENDS and vaping products changes the phenotype and function of AMs and suppresses their efferocytotic activity that helps clear the insult. Hence, reduced efferocytosis will lead to impaired resolution of inflammation. In addition, other cell types including AMs (polarization M1 and M2), PMNs, and AECs are involved in inhaled irritant-induced lung injurious responses.

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Figure 1
Interaction of ENDS use or vaping generated aerosols/lipids with the airway innate immune cells. The inhaled vapors/aerosols from ENDS use that consists of the hydrocarbons like oil and lipids, vitamin E acetate (VEA) and heavy metals end up in the alveolar regions where active efferocytosis of these aerosolized constituents leads to accumulation of lipid-laden AMs (Lipoid AMs or Foam cells) and the NET-release from the PMNs. The oxidative damage also the leads to the aggregation of oxidative derivatives of the cellular lipids and the surfactants. The AT-II cells secrete inflammatory factors and lung surfactants in the ELF, AMs, alveolar macrophages; AT-1, Alveolar type-1 cells; AT-2, Alveolar type-2 cells; PMNs, polymorphonuclear cells; NETs, neutrophil extracellular traps.

Several pathophysiological alterations in the lung functions have been associated with E-Cig exposure both in humans and in animal model studies with the reported effects on the airway mucociliary clearance and dysreglated repair mechanisms. In E-Cig users a reduced pulmonary function is often observed that is evaluated by the forced expiratory volume in one second (FEV1) and the ratio of forced expiratory volume to forced vital capacity (FEV/FVC) (Staudt et al., 2018; Meo et al., 2019).

Among E-Cig users, a significant increase in MUC4, a membrane-anchored mucin, and an increase in the ratio of secretory mucins MUC5AC to MUC5B has been reported compared to non-smoking participants (Reidel et al., 2018). A cross-sectional study suggested inflammasome complex proteins, caspase-1 and apoptosis-associated speck-like protein containing caspase activation and recruitment domain (ASC), which promote cellular pyroptosis, are elevated in the BAL fluid of E-Cig users (Tsai et al., 2019).

In a limited clinical study, higher serum club cell protein 16 (CC16) levels were strongly correlated in frequent E-Cig users compared to occasional smokers, reflecting epithelial dysfunction/injury in the lungs (Chaumont et al., 2019). In patients with EVALI, there was a higher concentration of serum C-reactive protein (Kalininskiy et al., 2019).

Some studies have reported increased inflammatory cell influx in the lung of patients with EVALI (Butt et al., 2019; Layden et al., 2019; Navon et al., 2019; Triantafyllou et al., 2019). In another study, the nasal scrapes from the E-Cig users showed significantly altered expression of early growth response (EGR1), ZBTB16, PIGR, PTGS2, and FKBP5 compared to the occasional E-Cig users with reduced CSF-1, CCL26, and eotaxin-3 levels that are essential for the mucosal host-defense (Martin et al., 2016). A comprehensive biomarker study showed alterations in several inflammatory and oxidative stress mediators in various biological fluids of E-Cig users (Singh et al., 2019). Additional comprehensive, cross-sectional and longitudinal studies are needed to fully establish the toxicity and the pathophysiology of the ENDS product exposure, especially differentially between e-cig nicotine vs THC product vaping on human health.

Clinical data, comprehensive or restrictive, on pulmonary toxicity are lacking; therefore, most of the understanding of the inhalational toxicity of E-Cig aerosol exposure comes from animal studies. In an acute (3 d) exposure mouse model of E-cig exposure, Lerner et al. demonstrated increased BALF IL-6 and CCL2 levels following Blu side-stream aerosol exposure (Lerner et al., 2015).

Pod-based e-juices and flavors also induce cellular toxicity with identification of several toxic chemicals (Muthumalage et al., 2019), hence this will render users susceptible to further damage as seen in EVALI cases. Similarly, Wang et al. reported dysregulated lung repair following E-cig exposure (Sundar et al., 2019). Whereas in a long-term exposure (3–6 mo) study using the two strains of mice, higher levels of Angiopoietin-1 and CXCL5 were observed along with lower MMP3 levels, indicating the involvement of the tissue-remodeling pathways (Crotty Alexander et al., 2018). Other rodent model studies have shown potential of DNA damage, adduct formation, and genotoxicity/carcinogenicity of E-Cig and vaping product aerosols (Lee et al., 2018).

Granulocytes, especially PMNs or neutrophils recruited to the injury site rapidly undergo degranulation and set extracellular traps (ETs) to curb the insult. Neutrophil-derived ETs (NETs) are extracellular fibers composed of DNA, histones, and granule-derived proteins such as elastase or myeloperoxidase derived by a process referred to as NETosis (Papayannopoulos, 2018).

NETs can trap extracellular irritants and be beneficial during infections to kill invading pathogens; however, aggregated NETs may cause adverse tissue injury to the host. Recently, E-Cig exposure in a mouse model was adversely associated with the increased susceptibility to a bacterial infection due to the disruption in PMNs and dysregulated NETosis (Corriden et al., 2019).

Resident monocytes and macrophages are also involved in resolving the NETs-mediated responses (Boe et al., 2015). Moreover, NETs also regulate AM polarization (M1 vs M2) to help mount appropriate immune response (Song et al., 2019).

References

  1. Beattie J. R., Schock B. C. (2009). Identifying the spatial distribution of vitamin E, pulmonary surfactant and membrane lipids in cells and tissue by confocal Raman microscopy. Methods Mol. Biol. 579, 513–535. 10.1007/978-1-60761-322-0_26 [PubMed] [CrossRef] [Google Scholar]
  2. Biondi-Zoccai G., Sciarretta S., Bullen C., Nocella C., Violi F., Loffredo L., et al. (2019). Acute effects of heat-not-burn, electronic vaping, and traditional tobacco combustion cigarettes: the Sapienza University of Rome-Vascular assessment of proatherosclerotic effects of smoking (SUR – VAPES) 2 randomized trial. J. Am. Heart Assoc. 8, e010455. 10.1161/JAHA.118.010455 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  3. Blagev D. P., Harris D., Dunn A. C., Guidry D. W., Grissom C. K., Lanspa M. J. (2019). Clinical presentation, treatment, and short-term outcomes of lung injury associated with e-cigarettes or vaping: a prospective observational cohort study. Lancet 10.1016/S0140-6736(19)32679-0 [PubMed] [CrossRef]
  4. Blount B. C., Karwowski M. P., Morel-Espinosa M., Rees J., Sosnoff C., Cowan E., et al. (2019. a). Evaluation of bronchoalveolar lavage fluid from patients in an outbreak of E-cigarette, or vaping, product use-associated lung injury – 10 States, August-October 2019. MMWR Morb Mortal Wkly Rep. 68, 1040–1041. 10.15585/mmwr.mm6845e2 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  5. Blount B. C., Karwowski M. P., Shields P. G., Morel-Espinosa M., Valentin-Blasini L., Gardner M., et al. (2019. b). Vitamin E Acetate in Bronchoalveolar-Lavage Fluid Associated with EVALI. N. Engl. J. Med. 10.1056/NEJMoa1916433 [PMC free article] [PubMed] [CrossRef]
  6. Boe D. M., Curtis B. J., Chen M. M., Ippolito J. A., Kovacs E. J. (2015). Extracellular traps and macrophages: new roles for the versatile phagocyte. J. Leukoc Biol. 97, 1023–1035. 10.1189/jlb.4RI1014-521R [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  7. Butt Y. M., Smith M. L., Tazelaar H. D., Vaszar L. T., Swanson K. L., Cecchini M. J., et al. (2019). Pathology of vaping-associated lung injury. N Engl. J. Med. 381, 1780–1781. 10.1056/NEJMc1913069 [PubMed] [CrossRef] [Google Scholar]
  8. Casanova G. S., Amaro R., Soler N., et al. (2019). An imported case of ecigarette or vaping associated lung injury (EVALI) in Barcelona. Eur. Respir. J. 10.1183/13993003.02076-2019 [PubMed] [CrossRef]
  9. Chatham-Stephens K., Roguski K., Jang Y., Cho P., Jatlaoui T. C., Kabbani S., et al. (2019). Characteristics of hospitalized and nonhospitalized patients in a nationwide outbreak of E-cigarette, or vaping, product use-associated lung injury – United States, November 2019. MMWR Morb Mortal Wkly Rep. 68, 1076–1080. 10.15585/mmwr.mm6846e1 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  10. Chaumont M., Van De Borne P., Bernard A., Van Muylem A., Deprez G., Ullmo J., et al. (2019). Fourth generation e-cigarette vaping induces transient lung inflammation and gas exchange disturbances: results from two randomized clinical trials. Am. J. Physiol. Lung Cell Mol. Physiol. 316, L705–L719. 10.1152/ajplung.00492.2018 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  11. Corriden R., Moshensky A., Bojanowski C. M., Meier A., Chien J., Nelson R. K., et al. (2019). E-Cigarette use increases susceptibility to bacterial infection by impairment of human neutrophil chemotaxis, phagocytosis and NET formation. Am. J. Physiol. Cell Physiol. 10.1152/ajpcell.00045.2019 [PMC free article] [PubMed] [CrossRef]
  12. Crotty Alexander L. E., Drummond C. A., Hepokoski M., Mathew D., Moshensky A., Willeford A., et al. (2018). Chronic inhalation of e-cigarette vapor containing nicotine disrupts airway barrier function and induces systemic inflammation and multiorgan fibrosis in mice. Am. J. Physiol. Regul. Integr. Comp. Physiol. 314, R834–R847. 10.1152/ajpregu.00270.2017 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  13. Cullen K. A., Ambrose B. K., Gentzke A. S., Apelberg B. J., Jamal A., King B. A. (2018). Notes from the field: use of electronic cigarettes and any tobacco product among middle and high school students – United States, 2011-2018. MMWR Morb Mortal Wkly Rep. 67, 1276–1277. 10.15585/mmwr.mm6745a5 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  14. Cullen K. A., Gentzke A. S., Sawdey M. D., Chang J. T., Anic G. M., Wang T. W., et al. (2019). E-cigarette use among youth in the United States, 2019. JAMA 322 (21), 2095–2103. 10.1001/jama.2019.18387 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  15. Gentzke A. S., Creamer M., Cullen K. A., Ambrose B. K., Willis G., Jamal A., et al. (2019). Vital signs: tobacco product use among middle and high school students – United States, 2011-2018. MMWR Morb Mortal Wkly Rep. 68, 157–164. 10.15585/mmwr.mm6806e1 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  16. Hybertson B. M., Kitlowski R. P., Jepson E. K., Repine J. E. (1998). Supercritical fluid-aerosolized vitamin E pretreatment decreases leak in isolated oxidant-perfused rat lungs. J. Appl. Physiol. 84, 263–268. 10.1152/jappl.1998.84.1.263 [PubMed] [CrossRef] [Google Scholar]
  17. Hybertson B. M., Chung J. H., Fini M. A., Lee Y. M., Allard J. D., Hansen B. N., et al. (2005). Aerosol-administered alpha-tocopherol attenuates lung inflammation in rats given lipopolysaccharide intratracheally. Exp. Lung Res. 31, 283–294. 10.1080/01902140590918560 [PubMed] [CrossRef] [Google Scholar]
  18. Jatlaoui T. C., Wiltz J. L., Kabbani S., Siegel D. A., Koppaka R., Montandon M., et al. (2019). Update: interim guidance for health care providers for managing patients with suspected E-cigarette, or vaping, product use-associated lung injury – United States, November 2019. MMWR Morb Mortal Wkly Rep. 68, 1081–1086. 10.15585/mmwr.mm6846e2 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  19. Kalininskiy A., Bach C. T., Nacca N. E., Ginsberg G., Marraffa J., Navarette K. A., et al. (2019). E-cigarette, or vaping, product use associated lung injury (EVALI): case series and diagnostic approach. Lancet Respir. Med. 7 (12), 1017–1026. 10.1016/S2213-2600(19)30415-1 [PubMed] [CrossRef] [Google Scholar]
  20. Khan M. S., Khateeb F., Akhtar J., Khan Z., Lal A., Kholodovych V., et al. (2018). Organizing pneumonia related to electronic cigarette use: a case report and review of literature. Clin. Respir. J. 12, 1295–1299. 10.1111/crj.12775 [PubMed] [CrossRef] [Google Scholar]
  21. Landman S. T., Dhaliwal I., Mackenzie C. A., Martinu T., Steele A., Bosma K. J. (2019). Life-threatening bronchiolitis related to electronic cigarette use in a Canadian youth. CMAJ 191 (48), E1321–E1331. 10.1503/cmaj.191402 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  22. Layden J. E., Ghinai I., Pray I., Kimball A., Layer M., Tenforde M., et al. (2019). Pulmonary illness related to E-cigarette use in Illinois and Wisconsin – preliminary report. N Engl. J. Med. 10.1056/NEJMoa1911614 [PubMed] [CrossRef]
  23. Lee H. W., Park S. H., Weng M. W., Wang H. T., Huang W. C., Lepor H., et al. (2018). E-cigarette smoke damages DNA and reduces repair activity in mouse lung, heart, and bladder as well as in human lung and bladder cells. Proc. Natl. Acad. Sci. U.S.A. 115, E1560–E1569. 10.1073/pnas.1718185115 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  24. Lerner C. A., Sundar I. K., Yao H., Gerloff J., Ossip D. J., Mcintosh S., et al. (2015). Vapors produced by electronic cigarettes and E-juices with flavorings induce toxicity, oxidative stress, and inflammatory response in lung epithelial cells and in mouse lung. PloS One 10, e0116732. 10.1371/journal.pone.0116732 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  25. Li C. X., Wheelock C. E., Skold C. M., Wheelock A. M. (2018). Integration of multi-omics datasets enables molecular classification of COPD. Eur. Respir. J. 51. 10.1183/13993003.01930-2017 [PubMed] [CrossRef] [Google Scholar]
  26. Madison M. C., Landers C. T., Gu B. H., Chang C. Y., Tung H. Y., You R., et al. (2019). Electronic cigarettes disrupt lung lipid homeostasis and innate immunity independent of nicotine. J. Clin. Invest. 129, 4290–4304. 10.1172/JCI128531 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  27. Martin E. M., Clapp P. W., Rebuli M. E., Pawlak E. A., Glista-Baker E., Benowitz N. L., et al. (2016). E-cigarette use results in suppression of immune and inflammatory-response genes in nasal epithelial cells similar to cigarette smoke. Am. J. Physiol. Lung Cell Mol. Physiol. 311, L135–L144. 10.1152/ajplung.00170.2016 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  28. Meo S. A., Ansary M. A., Barayan F. R., Almusallam A. S., Almehaid A. M., Alarifi N. S., et al. (2019). Electronic cigarettes: impact on lung function and fractional exhaled nitric oxide among healthy adults. Am. J. Mens Health 13, 1557988318806073. 10.1177/1557988318806073 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  29. Moritz E. D., Zapata L. B., Lekiachvili A., Glidden E., Annor F. B., Werner A. K., et al. (2019). Update: characteristics of patients in a national outbreak of E-cigarette, or vaping, product use-associated lung injuries – United States, October 2019. MMWR Morb Mortal Wkly Rep. 68, 985–989. 10.15585/mmwr.mm6843e1 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  30. Muthumalage T., Lamb T., Friedman M. R., Rahman I. (2019). E-cigarette flavored pods induce inflammation, epithelial barrier dysfunction, and DNA damage in lung epithelial cells and monocytes. Sci. Rep. 9, 19035. 10.1038/s41598-019-51643-6 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  31. Navon L., Jones C. M., Ghinai I., King B. A., Briss P. A., Hacker K. A., et al. (2019). Risk factors for E-cigarette, or vaping, product use-associated lung injury (EVALI) among adults who use E-cigarette, or vaping, products – Illinois, July-October 2019. MMWR Morb Mortal Wkly Rep. 68, 1034–1039. 10.15585/mmwr.mm6845e1 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  32. Papayannopoulos V. (2018). Neutrophil extracellular traps in immunity and disease. Nat. Rev. Immunol. 18, 134–147. 10.1038/nri.2017.105 [PubMed] [CrossRef] [Google Scholar]
  33. Perrine C. G., Pickens C. M., Boehmer T. K., King B. A., Jones C. M., Desisto C. L., et al. (2019). Characteristics of a multistate outbreak of lung injury associated with E-cigarette use, or vaping – United States, 2019. MMWR Morb Mortal Wkly Rep. 68, 860–864. 10.15585/mmwr.mm6839e1 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  34. Printz C. (2018). Food and drug administration takes steps to curb teen vaping. Cancer 124, 4431. 10.1002/cncr.31868 [PubMed] [CrossRef] [Google Scholar]
  35. Rehan H. S., Maini J., Hungin A. P. S. (2018). Vaping versus smoking: a quest for efficacy and safety of E-cigarette. Curr. Drug Saf. 13, 92–101. 10.2174/1574886313666180227110556 [PubMed] [CrossRef] [Google Scholar]
  36. Reidel B., Radicioni G., Clapp P. W., Ford A. A., Abdelwahab S., Rebuli M. E., et al. (2018). E-Cigarette use causes a unique innate immune response in the lung, involving increased neutrophilic activation and altered mucin secretion. Am. J. Respir. Crit. Care Med. 197, 492–501. 10.1164/rccm.201708-1590OC [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  37. Shukla P., Dwivedi P., Gupta P. K., Mishra P. R. (2014). Optimization of novel tocopheryl acetate nanoemulsions for parenteral delivery of curcumin for therapeutic intervention of sepsis. Expert Opin. Drug Delivery 11, 1697–1712. 10.1517/17425247.2014.932769 [PubMed] [CrossRef] [Google Scholar]
  38. Singh K. P., Lawyer G., Muthumalage T. G., Maremanda K. P., Khan N. A., McDonough S. R., et al. (2019). Systemic biomarkers in electronic cigarette users: implications for noninvasive assessment of vaping-associated pulmonary injuries. ERJ Open Res. 5 (4), 00182–2019. 10.1183/23120541.00182-2019 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  39. Sommerfeld C. G., Weiner D. J., Nowalk A., Larkin A. (2018). Hypersensitivity pneumonitis and acute respiratory distress syndrome from E-cigarette use. Pediatrics 141 (6), e20163927. 10.1542/peds.2016-3927 [PubMed] [CrossRef] [Google Scholar]
  40. Song C., Li H., Li Y., Dai M., Zhang L., Liu S., et al. (2019). NETs promote ALI/ARDS inflammation by regulating alveolar macrophage polarization. Exp. Cell Res. 382, 111486. 10.1016/j.yexcr.2019.06.031 [PubMed] [CrossRef] [Google Scholar]
  41. Staudt M. R., Salit J., Kaner R. J., Hollmann C., Crystal R. G. (2018). Altered lung biology of healthy never smokers following acute inhalation of E-cigarettes. Respir. Res. 19, 78. 10.1186/s12931-018-0778-z [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  42. Sundar I. K., Maremanda K. P., Rahman I. (2019). Mitochondrial dysfunction is associated with Miro1 reduction in lung epithelial cells by cigarette smoke. Toxicol. Lett. 317, 92–101. 10.1016/j.toxlet.2019.09.022 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  43. Taylor J., Wiens T., Peterson J., Saravia S., Lunda M., Hanson K., et al. (2019). Characteristics of E-cigarette, or vaping, products used by patients with associated lung injury and products aeized by law enforcement – Minnesota, 2018 and 2019. MMWR Morb Mortal Wkly Rep. 68, 1096–1100. 10.15585/mmwr.mm6847e1 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  44. Triantafyllou G. A., Tiberio P. J., Zou R. H., Lamberty P. E., Lynch M. J., Kreit J. W., et al. (2019). Vaping-associated acute lung injury: a case series. Am. J. Respir. Crit. Care Med. 200, 11. 10.1164/rccm.201909-1809LE [PubMed] [CrossRef] [Google Scholar]
  45. Tsai M., Song M. A., Mcandrew C., Brasky T. M., Freudenheim J. L., Mathe E., et al. (2019). Electronic versus combustible cigarette effects on inflammasome component release into human lung. Am. J. Respir. Crit. Care Med. 199, 922–925. 10.1164/rccm.201808-1467LE [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  46. Viswam D., Trotter S., Burge P. S., Walters G. I. (2018). Respiratory failure caused by lipoid pneumonia from vaping e-cigarettes. BMJ Case Rep. 2018. 10.1136/bcr-2018-224350 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  47. Wang S., Sun N. N., Zhang J., Watson R. R., Witten M. L. (2002). Immunomodulatory effects of high-dose alpha-tocopherol acetate on mice subjected to sidestream cigarette smoke. Toxicology 175, 235–245. 10.1016s0300-483x(02)00064-1 [PubMed] [Google Scholar]
  48. Wang T. W., Asman K., Gentzke A. S., Cullen K. A., Holder-Hayes E., Reyes-Guzman C., et al. (2018). Tobacco product use among adults – United States, 2017. MMWR Morb Mortal Wkly Rep. 67, 1225–1232. 10.15585/mmwr.mm6744a2 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  49. Ween M. P., Hamon R., Macowan M. G., Thredgold L., Reynolds P. R., Hodge S. J. (2019). Effects of E-cigarette E-liquid components on bronchial epithelial cells: Demonstration of dysfunctional efferocytosis. Respirology 2019, 1–9. 10.1111/resp.13696 [PubMed] [CrossRef] [Google Scholar]
  50. Xue Y., Williams T. L., Li T., Umbehr J., Fang L., Wang W., et al. (2005). Type II pneumocytes modulate surfactant production in response to cigarette smoke constituents: restoration by vitamins A and E. Toxicol. Vitro 19, 1061–1069. 10.1016/j.tiv.2005.05.003 [PubMed] [CrossRef] [Google Scholar]

More information: Tina Bormann et al. Role of the COX2-PGE2 axis in S. pneumoniae induced exacerbation of experimental fibrosis, American Journal of Physiology-Lung Cellular and Molecular Physiology (2020). DOI: 10.1152/ajplung.00024.2020

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