Biomarkers of Airway Immune Homeostasis Differ Significantly with Generation of E-Cigarettes

Hickman, Elise; Payton, Alexis; Duffney, Parker F.; Wells, Heather; Ceppe, Agathe; Brocke, Stephanie A.; Bailey, Aleah; Rebuli, Meghan E.; Robinette, Carole; Ring, Brian; Rager, Julia E.; Alexis, Neil E.; Jaspers, Ilona

doi:10.1164/rccm.202202-0373oc

Cited by 16 publications

(19 citation statements)

References 47 publications

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“…Although one may conclude that these data support that the use of fourth generation ENDS as being ‘safer’ for human health compared to the use of tank-style ENDS devices, thus far, human and experimental evidence show differential responses following exposures to these distinct types of ENDS devices. It was recently shown it a study using sputum of smokers, third-generation e-cig users, fourth-generation e-cig users, and non-smokers (controls), that the use of fourth-generation ENDS, containing high nicotine salt levels (35 to 59 mg/mL), induced a distinct suppressive immune disruptive pattern in the lungs compared to the use of ENDS from previous generations and even from cigarettes [ 4 ]. Thus, it was proposed that nicotine salt drove the immunosuppressive responses in the lungs [ 4 ].…”

Section: Discussionmentioning

confidence: 99%

“…It was recently shown it a study using sputum of smokers, third-generation e-cig users, fourth-generation e-cig users, and non-smokers (controls), that the use of fourth-generation ENDS, containing high nicotine salt levels (35 to 59 mg/mL), induced a distinct suppressive immune disruptive pattern in the lungs compared to the use of ENDS from previous generations and even from cigarettes [ 4 ]. Thus, it was proposed that nicotine salt drove the immunosuppressive responses in the lungs [ 4 ]. This contrasts with the presence of high aldehyde levels found in third-generation ENDS aerosols, which are known to affect cytotoxicity, inflammation and oxidative stress pathways in lung cells [ 13 , 37 ].…”

Section: Discussionmentioning

confidence: 99%

“…Little, however, is known regarding the health effects induced by chronic inhalation of ENDS aerosols produced by third or fourth generations ENDS devices. These aerosols are composed of heated nicotine, either in the freebase or salt forms, flavoring chemicals, and humectants, including propylene glycol (PG) and glycerol (G) [ 4 ]. The rapid, recent increase in ENDS use is a major two-pronged public health concern, with alarming numbers of users among adults and vulnerable populations, including youth, and inadequate information on long-term pulmonary responses to ENDS aerosol exposures.…”

Section: Introductionmentioning

confidence: 99%

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Carbonyl Profiles of Electronic Nicotine Delivery System (ENDS) Aerosols Reflect Both the Chemical Composition and the Numbers of E-Liquid Ingredients–Focus on the In Vitro Toxicity of Strawberry and Vanilla Flavors

Noël¹,

Ghosh²

2022

IJERPH

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Propylene glycol (PG) and glycerin (G) are the most widely used humectants in electronic nicotine delivery system (ENDS) devices. Carbonyls are present in aerosols produced when ENDS devices heat PG and G. Whether aerosolized PG and G are innocuous to the lungs has not been established. Here, we determined the chemical profiles of ENDS aerosols containing three humectant ratios (30/70, 50/50 and 70/30, PG/VG), for three flavors (strawberry, vanilla and Catalan cream) containing either 12 or 18 mg/mL of nicotine. Additionally, we examined the in vitro toxicity of the strawberry- and vanilla-flavored ENDS aerosol in human lung epithelial cells (BEAS-2B) exposed at the air-liquid interface for 1 h. For strawberry- and vanilla-flavored aerosols produced by a 3rd-generation ENDS device with the same PG/G ratio, the e-liquid nicotine content of 12 and 18 mg/mL did not transfer to the aerosol with substantial differences in concentrations. Our data also indicate the presence of carbonyls in all three flavored e-cig aerosols analyzed, with levels exceeding 1 µg/puff for acetone, butyraldehyde, and acetaldehyde, in strawberry-, vanilla, and Catalan cream-flavored e-cig aerosols, respectively. Furthermore, closed-system ENDS of the fourth generation emitted trace levels of carbonyls in the aerosols (<0.3 µg/puff), while open-system tank-style ENDS of the third generation produced elevated levels of harmful chemicals, including acrolein (>1 µg/puff), formaldehyde (>5 µg/puff), and m- & p-tolualdehyde (>4 µg/puff). Moreover, under non-cytotoxic conditions, BEAS-2B cells exposed to strawberry-flavored aerosols exhibited significantly increased reactive oxygen and nitric oxide species (ROS/NOS) levels in cell media compared to air controls, while vanilla-flavored ENDS aerosols up-regulated the expression of pro-inflammatory and oxidative stress markers. Our data suggest (a) that ENDS aerosol chemical composition will vary based upon the presence and concentration of the initial e-liquid ingredients, with a pronounced impact of the flavoring components; and (b) short-term exposures to flavored ENDS aerosols may impair lung cells’ redox signaling in a flavor-specific manner.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Carbonyl Profiles of Electronic Nicotine Delivery System (ENDS) Aerosols Reflect Both the Chemical Composition and the Numbers of E-Liquid Ingredients–Focus on the In Vitro Toxicity of Strawberry and Vanilla Flavors

Noël¹,

Ghosh²

2022

IJERPH

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“…37 This clustering approach was implemented to identify groups of cytokines with concerted response profiles across exposure conditions, as previously described. 41,42 Correlation Analysis between Polyaromatic Hydrocarbons (PAHs) and Cytokine Levels. We used the PAH levels present in the smoldering and flaming condenstaes 15 and the cytokine levels to perform Spearman's rank correlation tests using the psych package 43 in R (v 4.3.2).…”

Section: Statistical Analysis Of Cytokine and Gene Expressionmentioning

confidence: 99%

Burn Pit Smoke Condensate-Mediated Toxicity in Human Airway Epithelial Cells

Ghosh,

Payton,

Gallant

et al. 2024

Chem. Res. Toxicol.

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Burn pits are a method of open-air waste management that was common during military operations in Iraq, Afghanistan, and other regions in Southwest Asia. Veterans returning from deployment have reported respiratory symptoms, potentially from exposure to burn pit smoke, yet comprehensive assessment of such exposure on pulmonary health is lacking. We have previously shown that exposure to condensates from burn pit smoke emissions causes inflammation and cytotoxicity in mice. In this study, we explored the effects of burn pit smoke condensates on human airway epithelial cells (HAECs) to understand their impact on cellular targets in the human lung. HAECs were cultured at the air–liquid interface (ALI) and exposed to burn pit waste smoke condensates (plywood, cardboard, plastic, mixed, and mixed with diesel) generated under smoldering and flaming conditions. Cytotoxicity was evaluated by measuring transepithelial electrical resistance (TEER) and lactate dehydrogenase (LDH) release; toxicity scores (TSs) were quantified for each exposure. Pro-inflammatory cytokine release and modulation of gene expression were examined for cardboard and plastic condensate exposures. Burn pit smoke condensates generated under flaming conditions affected cell viability, with flaming mixed waste and plywood exhibiting the highest toxicity scores. Cardboard and plastic smoke condensates modulated cytokine secretion, with GM-CSF and IL-1β altered in more than one exposure group. Gene expression of detoxifying enzymes (ALDH1A3, ALDH3A1, CYP1A1, CYP1B1, NQO1, etc.), mucins (MUC5AC, MUC5B), and cytokines was affected by several smoke condensates. Particularly, expression of IL6 was elevated following exposure to all burn pit smoke condensates, and polycyclic aromatic hydrocarbon acenaphthene was positively associated with the IL-6 level in the basolateral media of HAECs. These observations demonstrate that exposure to smoke condensates of materials present in burn pits adversely affects HAECs and that aberrant cytokine secretion and altered gene expression profiles following burn pit material smoke exposure could contribute to the development of airway disease.

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“…Limitations of Hickman's study include over-representation of males within the 4 th generation e-cigarette group, which the authors controlled for in their analysis. Beyond classifying ecigarette users by generation of device, the e-cigarette groups were not further characterized with regards to flavor, frequency or chronicity of use, or concomitant use of marijuanacontaining products 8 . This limitation highlights a challenge for the tobacco research community at large, to develop high quality, common survey instruments to accurately quantify concomitant combustible tobacco and marijuana use, as well as types, flavors and frequency of e-cigarettes and e-liquids used.…”

mentioning

confidence: 99%

A Problem for Generations: Impact of E-Cigarette Type on Immune Homeostasis

Sullivan

Alexander

2022

Am J Respir Crit Care Med

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smokers, 3 rd generation e-cigarette users, and 4 th generation e-cigarette users. The primary endpoint was differences in 45 soluble mediators associated with inflammation, host defense, and lung injury in sputum supernatant. Of 45 mediators evaluated, 12 had significant differences amongst groups. The authors found overall reduced levels of mediators in 4 th generation e-cigarette users, and specifically highlight lower concentrations of sICAM1 and sVCAM1 in 4 th generation e-cigarette users relative to non-smokers/non-vapers and 3 rd generation e-cigarette users. The authors suggest that these differences may indicate an overall suppression of host defense associated with 4 th generation e-cigarette use, and hypothesize this may be attributable to the inhalation of high concentration of nicotinic salts 8 . This study adds to the current body of literature that demonstrates significant alterations to the inflammatory and immune milieu associated with chronic e-cigarette use. In one study by Ghosh et al, combustible tobacco and e-cigarette smokers were found to have higher levels of proteases, including neutrophil elastase, matrix metalloprotease (MMP)-2, and MMP-9, in bronchoalveolar lavage samples compared to non-smokers/non-vapers, without a concomitant increase in anti-protease levels 9 . A study by Sayed et al evaluated sputum and saliva of nonsmokers/non-vapers to those of e-cigarette users and found a reduction in markers of airway inflammation in vapers. Interestingly, this study also examined plasma in both groups, and found higher circulating levels of certain inflammatory cytokines, chemokines, and growth factors in e-cigarette users, in particular TNF-β and VEGF, suggesting that changes in airway inflammatory markers may represent a counter-response to general inflammation caused by chronic e-cigarette use 10 . Reidel and colleagues evaluated induced sputum samples from combustible tobacco smokers, e-cigarette users, and non-smokers/non-vapers, and found elevated markers of neutrophil activation in e-cigarette users without an increase in absolute

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Biomarkers of Airway Immune Homeostasis Differ Significantly with Generation of E-Cigarettes

Cited by 16 publications

References 47 publications

Carbonyl Profiles of Electronic Nicotine Delivery System (ENDS) Aerosols Reflect Both the Chemical Composition and the Numbers of E-Liquid Ingredients–Focus on the In Vitro Toxicity of Strawberry and Vanilla Flavors

Carbonyl Profiles of Electronic Nicotine Delivery System (ENDS) Aerosols Reflect Both the Chemical Composition and the Numbers of E-Liquid Ingredients–Focus on the In Vitro Toxicity of Strawberry and Vanilla Flavors

Burn Pit Smoke Condensate-Mediated Toxicity in Human Airway Epithelial Cells

A Problem for Generations: Impact of E-Cigarette Type on Immune Homeostasis

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