RESUMEN
Introduction: Chronic obstructive pulmonary disease (COPD) is currently listed as the 3rd leading cause of death in the United States. Accumulating data shows the association between COPD occurrence and the usage of electronic nicotine delivery systems (ENDS) in patients. However, the underlying pathogenesis mechanisms of COPD have not been fully understood. Methods: In the current study, bENaC-overexpressing mice (bENaC mice) were subjected to whole-body ENDS exposure. COPD related features including emphysema, mucus accumulation, inflammation and fibrosis are examined by tissue staining, FACS analysis, cytokine measurement. Cell death and ferroptosis of alveolar epithelial cells were further evaluated by multiple assays including staining, FACS analysis and lipidomics. Results: ENDS-exposed mice displayed enhanced emphysema and mucus accumulation, suggesting that ENDS exposure promotes COPD features. ENDS exposure also increased immune cell number infiltration in bronchoalveolar lavage and levels of multiple COPD-related cytokines in the lungs, including CCL2, IL-4, IL-13, IL-10, M-CSF, and TNF-α. Moreover, we observed increased fibrosis in ENDS-exposed mice, as evidenced by elevated collagen deposition and a-SMA+ myofibroblast accumulation. By investigating possible mechanisms for how ENDS promoted COPD, we demonstrated that ENDS exposure induced cell death of alveolar epithelial cells, evidenced by TUNEL staining and Annexin V/PI FACS analysis. Furthermore, we identified that ENDS exposure caused lipid dysregulations, including TAGs (9 species) and phospholipids (34 species). As most of these lipid species are highly associated with ferroptosis, we confirmed ENDS also enhanced ferroptosis marker CD71 in both type I and type II alveolar epithelial cells. Discussion: Overall, our data revealed that ENDS exposure exacerbates features of COPD in bENaC mice including emphysema, mucus accumulation, abnormal lung inflammation, and fibrosis, which involves the effect of COPD development by inducing ferroptosis in the lung.
Asunto(s)
Cigarrillo Electrónico a Vapor , Ferroptosis , Nicotina , Enfermedad Pulmonar Obstructiva Crónica , Animales , Enfermedad Pulmonar Obstructiva Crónica/inducido químicamente , Enfermedad Pulmonar Obstructiva Crónica/patología , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Enfermedad Pulmonar Obstructiva Crónica/etiología , Ratones , Nicotina/efectos adversos , Nicotina/toxicidad , Nicotina/administración & dosificación , Cigarrillo Electrónico a Vapor/efectos adversos , Modelos Animales de Enfermedad , Citocinas/metabolismo , Ratones Endogámicos C57BL , Sistemas Electrónicos de Liberación de Nicotina , Masculino , Ratones TransgénicosRESUMEN
Exposure to cigarette smoke is known to induce disease during pregnancy. Recent evidence showed that exposure to secondhand smoke (SHS) negatively impacts fetal and placental weights, leading to the development of intrauterine growth restriction (IUGR). Electronic cigarettes (eCigs) represent a phenomenon that has recently emerged, and their use is also steadily rising. Even so, the effects of SHS or eCigs during gestation remain limited. In the present study, we wanted to characterize the effects of SHS or eCig exposure at two different important gestational points during mouse pregnancy. C57/Bl6 mice were exposed to SHS or eCigs via a nose-only delivery system for 4 days (from 14.5 to 17.5 gestational days (dGA) or for 6 days (from 12.5 dGA to 17.5 dGA)). At the time of necropsy (18.5 dGA), placental and fetal weights were recorded, maternal blood pressure was determined, and a dipstick test to measure proteinuria was performed. Placental tissues were collected, and inflammatory molecules in the placenta were identified. Treatment with SHS showed the following: (1) a significant decrease in placental and fetal weights following four days of exposure, (2) higher systolic and diastolic blood pressure following six days of exposure, and (3) increased proteinuria after six days of exposure. Treatment with eCigs showed the following: (1) a significant decrease in placental weight and fetal weight following four or six days of exposure, (2) higher systolic and diastolic blood pressure following six days of exposure, and (3) increased proteinuria after six days of exposure. We also observed different inflammatory markers associated with the development of IUGR or PE. We conclude that the detrimental effects of SHS or eCig treatment coincide with the length of maternal exposure. These results could be beneficial in understanding the long-term effects of SHS or eCig exposure in the development of placental diseases.
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Ratones Endogámicos C57BL , Placenta , Contaminación por Humo de Tabaco , Embarazo , Femenino , Animales , Contaminación por Humo de Tabaco/efectos adversos , Ratones , Placenta/efectos de los fármacos , Placenta/patología , Enfermedades Placentarias/patología , Enfermedades Placentarias/inducido químicamente , Cigarrillo Electrónico a Vapor/efectos adversos , Exposición Materna/efectos adversos , Presión Sanguínea/efectos de los fármacos , Retardo del Crecimiento Fetal/inducido químicamente , Sistemas Electrónicos de Liberación de NicotinaRESUMEN
E-cigarette users predominantly also continue to smoke cigarettes. These Dual Users either consume e-cigarettes in locations where smoking is not allowed, but vaping is, or to reduce their consumption of cigarettes, believing it will lead to harm reduction. Whilst it is known that e-cigarette vapour is chemically less complex than cigarette smoke, it has a distinct chemical profile, and very little is known about the health impacts of exposure to both chemical profiles vs. either alone. We simultaneously exposed cells in vitro to non-toxic levels of e-cigarette vapour extract (EVE) and cigarette smoke extract (CSE) to determine their effects on 16HBE14o- airway epithelial cell metabolism and inflammatory response, as well as immune cell (THP-1 cells and monocyte-derived macrophages (MDM) from healthy volunteers) migration, phagocytosis, and inflammatory response. We observed increased toxicity, reduced metabolism (a marker of proliferation) in airway epithelial cells, and reduced monocyte migration, macrophage phagocytosis, and altered chemokine production after exposure to either CSE or EVE. These cellular responses were greater after dual exposure to CSE and EVE. The airway epithelial cells from smokers showed reduced metabolism after EVE (the Switcher model) and dual CSE and EVE exposure. When EVE and CSE were allowed to interact, the chemicals were found to be altered, and new chemicals were also found compared to the CSE and EVE profiles. Dual exposure to e-cigarette vapour and cigarette smoke led to worse functional outcomes in cells compared to either single exposure alone, adding to limited data that dual use may be more dangerous than smoking only.
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Sistemas Electrónicos de Liberación de Nicotina , Macrófagos , Monocitos , Humanos , Macrófagos/metabolismo , Macrófagos/efectos de los fármacos , Monocitos/metabolismo , Monocitos/efectos de los fármacos , Humo/efectos adversos , Células Epiteliales/metabolismo , Células Epiteliales/efectos de los fármacos , Cigarrillo Electrónico a Vapor/efectos adversos , Vapeo/efectos adversos , Fagocitosis/efectos de los fármacos , Células THP-1 , Movimiento Celular/efectos de los fármacos , Fumar/efectos adversos , Productos de Tabaco/efectos adversosRESUMEN
Cigarette smoking is positively and robustly associated with cardiovascular disease (CVD), including hypertension, atherosclerosis, cardiac arrhythmias, stroke, thromboembolism, myocardial infarctions, and heart failure. However, after more than a decade of ENDS presence in the U.S. marketplace, uncertainty persists regarding the long-term health consequences of ENDS use for CVD. New approach methods (NAMs) in the field of toxicology are being developed to enhance rapid prediction of human health hazards. Recent technical advances can now consider impact of biological factors such as sex and race/ethnicity, permitting application of NAMs findings to health equity and environmental justice issues. This has been the case for hazard assessments of drugs and environmental chemicals in areas such as cardiovascular, respiratory, and developmental toxicity. Despite these advances, a shortage of widely accepted methodologies to predict the impact of ENDS use on human health slows the application of regulatory oversight and the protection of public health. Minimizing the time between the emergence of risk (e.g., ENDS use) and the administration of well-founded regulatory policy requires thoughtful consideration of the currently available sources of data, their applicability to the prediction of health outcomes, and whether these available data streams are enough to support an actionable decision. This challenge forms the basis of this white paper on how best to reveal potential toxicities of ENDS use in the human cardiovascular system-a primary target of conventional tobacco smoking. We identify current approaches used to evaluate the impacts of tobacco on cardiovascular health, in particular emerging techniques that replace, reduce, and refine slower and more costly animal models with NAMs platforms that can be applied to tobacco regulatory science. The limitations of these emerging platforms are addressed, and systems biology approaches to close the knowledge gap between traditional models and NAMs are proposed. It is hoped that these suggestions and their adoption within the greater scientific community will result in fresh data streams that will support and enhance the scientific evaluation and subsequent decision-making of tobacco regulatory agencies worldwide.
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Enfermedades Cardiovasculares , Sistemas Electrónicos de Liberación de Nicotina , Vapeo , Humanos , Medición de Riesgo , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/inducido químicamente , Enfermedades Cardiovasculares/prevención & control , Animales , Vapeo/efectos adversos , Vapeo/tendencias , Factores de Riesgo , Nicotina/efectos adversos , Nicotina/administración & dosificación , Agonistas Nicotínicos/efectos adversos , Agonistas Nicotínicos/administración & dosificación , Agonistas Nicotínicos/toxicidad , Seguridad de Productos para el Consumidor , Sistema Cardiovascular/efectos de los fármacos , Cardiotoxicidad , Factores de Riesgo de Enfermedad Cardiaca , Cigarrillo Electrónico a Vapor/efectos adversosRESUMEN
Smoking cigarettes during pregnancy is associated with adverse effects on infants including low birth weight, defective lung development, and skeletal abnormalities. Pregnant women are increasingly turning to vaping [use of electronic (e)-cigarettes] as a perceived safer alternative to cigarettes. However, nicotine disrupts fetal development, suggesting that like cigarette smoking, nicotine vaping may be detrimental to the fetus. To test the impact of maternal vaping on fetal lung and skeletal development in mice, pregnant dams were exposed to e-cigarette vapor throughout gestation. At embryonic day (E)18.5, vape exposed litter sizes were reduced, and some embryos exhibited growth restriction compared to air exposed controls. Fetal lungs were collected for histology and whole transcriptome sequencing. Maternally nicotine vaped embryos exhibited histological and transcriptional changes consistent with impaired distal lung development. Embryonic lung gene expression changes mimicked transcriptional changes observed in adult mouse lungs exposed to cigarette smoke, suggesting that the developmental defects may be due to direct nicotine exposure. Fetal skeletons were analyzed for craniofacial and long bone lengths. Nicotine directly binds and inhibits the Kcnj2 potassium channel which is important for bone development. The length of the maxilla, palatal shelves, humerus, and femur were reduced in vaped embryos, which was further exacerbated by loss of one copy of the Kcnj2 gene. Nicotine vapor exposed Kcnj2KO/+ embryos also had significantly lower birth weights than unexposed animals of either genotype. Kcnj2 mutants had severely defective lungs with and without vape exposure, suggesting that potassium channels may be broadly involved in mediating the detrimental developmental effects of nicotine vaping. These data indicate that intrauterine nicotine exposure disrupts fetal lung and skeletal development likely through inhibition of Kcnj2.
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Cigarrillo Electrónico a Vapor , Sistemas Electrónicos de Liberación de Nicotina , Vapeo , Femenino , Embarazo , Animales , Humanos , Ratones , Vapeo/efectos adversos , Nicotina/efectos adversos , Nicotina/metabolismo , Pulmón/metabolismo , Cigarrillo Electrónico a Vapor/efectos adversosRESUMEN
BACKGROUND: Electronic cigarette (e-cigarette) vapour is gaining popularity as an alternative to tobacco smoking and can induce acute lung injury. However, the specific role of nicotine in e-cigarette vapour and its long-term effects on the airways, lung parenchyma and vasculature remain unclear. RESULTS: In vitro exposure to nicotine-containing e-cigarette vapour extract (ECVE) or to nicotine-free e-cigarette vapour extract (NF ECVE) induced changes in gene expression of epithelial cells and pulmonary arterial smooth muscle cells (PASMCs), but ECVE in particular caused functional alterations (e.g. a decrease in human and mouse PASMC proliferation by 29.3±5.3% and 44.3±8.4%, respectively). Additionally, acute inhalation of nicotine-containing e-cigarette vapour (ECV) but not nicotine-free e-cigarette vapour (NF ECV) increased pulmonary endothelial permeability in isolated lungs. Long-term in vivo exposure of mice to ECV for 8â months significantly increased the number of inflammatory cells, in particular lymphocytes, compared to control and NF ECV in the bronchoalveolar fluid (BALF) (ECV: 853.4±150.8â cells·mL-1; control: 37.0±21.1â cells·mL-1; NF ECV: 198.6±94.9â cells·mL-1) and in lung tissue (ECV: 25.7±3.3â cells·mm-3; control: 4.8±1.1â cells·mm-3; NF ECV: 14.1±2.2â cells·mm-3). BALF cytokines were predominantly increased by ECV. Moreover, ECV caused significant changes in lung structure and function (e.g. increase in airspace by 17.5±1.4% compared to control), similar to mild tobacco smoke-induced alterations, which also could be detected in the NF ECV group, albeit to a lesser degree. In contrast, the pulmonary vasculature was not significantly affected by ECV or NF ECV. CONCLUSIONS: NF ECV components induce cell type-specific effects and mild pulmonary alterations, while inclusion of nicotine induces significant endothelial damage, inflammation and parenchymal alterations.
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Cigarrillo Electrónico a Vapor , Sistemas Electrónicos de Liberación de Nicotina , Neumonía , Humanos , Animales , Ratones , Nicotina/efectos adversos , Cigarrillo Electrónico a Vapor/efectos adversos , Cigarrillo Electrónico a Vapor/metabolismo , Neumonía/etiología , Neumonía/metabolismo , Pulmón/metabolismo , Extractos Vegetales/metabolismo , Extractos Vegetales/farmacologíaRESUMEN
Electronic cigarette use is highest among adults of child-bearing age. Many parents that use electronic cigarettes believe that secondhand exposure of electronic cigarette vapors for their children is not dangerous and is less harmful than secondhand exposure to traditional cigarette smoke. These beliefs may prompt excessive secondhand exposure to electronic cigarette vapors for their children. Little research has been done to document exposure in children. The traditional biological method of exposure detection is through a blood draw, which is difficult and undesirable in children. The purpose of this study was to assess the feasibility of using saliva and exhaled breath condensate as non-invasive biomatrices for detecting secondhand electronic cigarette vapor exposure in children. In this cross-sectionally designed study, we recruited 22 children exposed to electronic cigarette vapors and 26 non-exposed between the ages of 4-12 years. We compared metabolic features across three biomatrices, blood, saliva, and exhaled breath condensate. We noted moderate to strong pairwise, sample-specific, and feature-specific adjusted correlations. Annotated features associated with direct and secondhand electronic cigarette exposure were noted. These results demonstrate that less invasive biomatrices may be used to detect features associated with secondhand electronic cigarette vapor exposure in children.
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Cigarrillo Electrónico a Vapor , Sistemas Electrónicos de Liberación de Nicotina , Contaminación por Humo de Tabaco , Adulto , Niño , Preescolar , Humanos , Cigarrillo Electrónico a Vapor/efectos adversos , Proyectos Piloto , Saliva , Contaminación por Humo de Tabaco/efectos adversos , MetabolómicaRESUMEN
O cigarro eletrônico surgiu como uma tentativa para minimizar a dependência ao uso de tabaco, entretanto, engloba controvérsias e dúvidas acerca das reais implicações para o organismo humano. Diante disso, o presente estudo tem como objetivo realizar uma revisão da literatura a fim de relacionar o uso de cigarro eletrônico com suas consequências para os humanos. Os estudos analisados relatam experimentos in vitro e in vivo em camundongos, demonstrando menor concentração de poluentes e nocividades no cigarro eletrônico comparado ao convencional, porém, seu potencial efeito maléfico está relacionado à composição do e-líquido, à maneira do uso e à variedade de aromas presentes nos produtos. Além disso, foram verificadas lesões celulares, hiperreatividade das vias aéreas, liberação de citocinas IL-8, IL-10 e TNF, redução da ação antimicrobiana de queratinócitos e potencial apoptose nas células alveolares. Foi observado também um aumento em até cinco vezes da concentração de carboxihemoglobina em comparação ao cigarro comum e um aumento na auto renovação de células de adenocarcinoma pulmonar de células não pequenas, devido à expressão de SOX2. Observa-se também que em casos de DPOC, o cigarro eletrônico não apresenta agravamentos na fisiologia respiratória, contrapondo outras ocorrências como asma, pneumonia, câncer de pulmão e doenças infecciosas que podem ser ocasionadas ou exacerbadas pelo seu uso. Contudo, pelo curto prazo de observação de seus efeitos, não é possível determinar com precisão a segurança dos cigarros eletrônicos, dessa forma, faz-se necessário que mais pesquisas longitudinais sejam desenvolvidas, auxiliando, assim, na construção de evidências sobre a segurança dos cigarros eletrônicos e na regulamentação futura do produto.
Electronic cigarettes emerged as an attempt to minimize tobacco dependence. However, its use is surrounded by controversies and doubts about the real implications for the human organism. Therefore, this study aims at performing a review of the most recent literature to corelate the use of e-cigarettes with their consequences for the human body. The analyzed studies relate in vitro and in vivo experiments on mice, demonstrating lower concentration of pollutants and harmfulness in the electronic cigarette than in conventional cigarettes. However, its potential harmful effect is related to the composition of the e-liquid, in its use and in the variety of aromas in the products. In addition, cellular lesions, airway hyperreactivity, release of IL-8, IL-10 and TNF cytokines could be observed, as well as reduced keratinocyte antimicrobial action and potential apoptosis in alveolar cells. An increase of up to five-fold the concentration of carboxyhemoglobin in comparison to ordinary cigarettes and an increase in self-renewal of non-small pulmonary adenocarcinoma cells due to the expression of SOX2 have also been related. It could also be observed that in COPD cases, e-cigarettes do not present worsening in respiratory physiology, which contrasts with other occurrences such as asthma, pneumonia, lung cancer, and infectious diseases that can be caused or exacerbated by its use. However, due to the short term of observation of the effects, the safety of e-cigarettes could not be accurately determined, thus, the need for further longitudinal research is necessary, which could be used to help build evidence about the safety of e-cigarettes and also to create future regulation of the product.
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Animales , Ratones , Ratas , Sistemas Electrónicos de Liberación de Nicotina/instrumentación , Enfermedades Pulmonares , Neumonía/complicaciones , Asma/complicaciones , Tabaquismo/complicaciones , Fumar , Enfermedad , Lesión Pulmonar , Uso de Tabaco , Vapeo , Fumadores , Cigarrillo Electrónico a Vapor/efectos adversos , Neoplasias PulmonaresRESUMEN
OBJECTIVES: To evaluate histologic changes in middle ear and eustachian tube (ET) mucosa of mice after exposure to tobacco or electronic cigarette (e-cigarette) smoke. To determine whether there were any mitigating effects of middle ear application of anti-IL-13 or the epidermal growth factor receptor antagonist AG1478 on noted changes within ET mucosa. STUDY DESIGN: Controlled animal study. METHODS: Fifty BALB/cJ mice were randomly assigned to one of five groups: A control group with no smoke exposure, two groups exposed to tobacco smoke, and two groups exposed to e-cigarette vapor. Within the exposed groups after 4 weeks of exposure, one ear was infiltrated with a saline hydrogel and the other ear with hydrogel of either Anti-IL-13 or AG1478. After four more weeks of exposure, the animals were euthanized and the ETs were evaluated for mucosal changes. RESULTS: Compared to control animals with no smoke exposure, there were significant decreases in the numbers of goblet cells within the ET mucosa of mice exposed to tobacco smoke and e-cigarette vapor. No significant differences in cilia, mucin, or squamous metaplasia were noted. Neither anti-IL-13 nor AG178 significantly altered goblet cell count in the ET mucosa of mice exposed to tobacco smoke; however, both agents significantly increased goblet cells within the ET mucosa of mice exposed to e-cigarette vapor. CONCLUSION: Short-term tobacco smoke and e-cigarette vapor significantly decrease goblet cell count in mouse ET mucosa. Middle ear application of both anti-IL-13 and AG1478 resulted in an increase in goblet cell count among mice exposed to e-cigarette vapor, but not to tobacco smoke. LEVEL OF EVIDENCE: NA Laryngoscope, 132:648-654, 2022.
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Cigarrillo Electrónico a Vapor/efectos adversos , Trompa Auditiva/efectos de los fármacos , Membrana Mucosa/efectos de los fármacos , Contaminación por Humo de Tabaco/efectos adversos , Animales , Sistemas Electrónicos de Liberación de Nicotina , Femenino , Células Caliciformes/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos BALB CRESUMEN
Objective: This study is the first to examine the influence of e-cigarette emission phrasing on perceived harm of secondhand exposure, and whether harm perception was associated with support for a tobacco-free campus policy. Participants: In the fall 2018 and spring 2019 semesters, 52 sections of a college English course (N = 791 students) were cluster randomized to one of three conditions ("vapor," "aerosol," or "chemicals") assessing harm of secondhand exposure to e-cigarette emissions. Methods: Regression models adjusted for demographic characteristics, tobacco use, and other potential confounders. Results: Compared to the "vapor" condition, "chemicals" and "aerosol" conditions were associated with increased odds of perceiving secondhand exposure to e-cigarettes to be harmful/very harmful (AOR = 2.0, p < 0.01). Greater perceived harm of secondhand e-cigarette exposure was associated with increased odds of supporting a tobacco-free campus policy (AOR = 2.22, p < 0.001). Conclusions: Health campaigns should use accurate terminology to describe e-cigarette emissions, rather than jargon that conveys lower risk.
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Sistemas Electrónicos de Liberación de Nicotina , Conocimientos, Actitudes y Práctica en Salud , Política para Fumadores , Estudiantes , Contaminación por Humo de Tabaco , Aerosoles/efectos adversos , Cigarrillo Electrónico a Vapor/efectos adversos , Humanos , Estudiantes/psicología , Contaminación por Humo de Tabaco/efectos adversos , Contaminación por Humo de Tabaco/prevención & control , UniversidadesRESUMEN
BACKGROUND: Electronic-cigarette (e-cig) usage, particularly in the youth population, is a growing concern. It is known that e-cig causes endothelial dysfunction, which is a risk factor for the development of cardiovascular diseases; however, the mechanisms involved remain unclear. We hypothesized that long noncoding RNAs (lncRNAs) may play a role in e-cig-induced endothelial dysfunction. METHODS: Here, we identified lncRNAs that are dysregulated in human induced pluripotent stem cell-derived endothelial cells (iPSC-ECs) following 24 h of e-cig aerosol extract treatment via microarray analysis. We performed Gene Ontology and Kyoto Encyclopedia of Genes and Genome (KEGG) pathway analyses of the dysregulated mRNAs following e-cig exposure and constructed co-expression networks of the top 5 upregulated lncRNAs and the top 5 downregulated lncRNAs and the mRNAs that are correlated with them. Furthermore, the functional effects of knocking down lncRNA lung cancer-associated transcript 1 (LUCAT1) on EC phenotypes were determined as it was one of the significantly upregulated lncRNAs following e-cig exposure based on our profiling. RESULTS: 183 lncRNAs and 132 mRNAs were found to be upregulated, whereas 297 lncRNAs and 413 mRNAs were found to be downregulated after e-cig exposure. We also observed that e-cig caused dysregulation of endothelial metabolism resulting in increased FAO activity, higher mitochondrial membrane potential, and decreased glucose uptake and glycolysis. These results suggest that e-cig alters EC metabolism by increasing FAO to compensate for energy deficiency in ECs. Finally, the knockdown of LUCAT1 prevented e-cig-induced EC dysfunction by maintaining vascular barrier, reducing reactive oxygen species level, and increasing migration capacity. CONCLUSION: This study identifies an expression profile of differentially expressed lncRNAs and several potential regulators and pathways in ECs exposed to e-cig, which provide insights into the regulation of lncRNAs and mRNAs and the role of lncRNA and mRNA networks in ECs associated e-cig exposure.
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Cigarrillo Electrónico a Vapor , Sistemas Electrónicos de Liberación de Nicotina , Células Madre Pluripotentes Inducidas , ARN Largo no Codificante , ARN Mensajero , Cigarrillo Electrónico a Vapor/efectos adversos , Células Endoteliales/metabolismo , Perfilación de la Expresión Génica , Ontología de Genes , Redes Reguladoras de Genes , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , ARN Largo no Codificante/genética , ARN Mensajero/genéticaRESUMEN
OBJECTIVES: Vaping products continue to remain popular among teens and young adults despite an overall lack of research regarding their potential health effects. While much research focuses on respiratory effects associated with electronic cigarette use, their effects on other systems, including embryonic cardiovascular function and development due to maternal use during pregnancy, also needs to be evaluated. Here, we assessed the impact of nicotine-free, cinnamon and chocolate flavored, electronic cigarette vapor on cardiovascular function during early development by exposing wild-type zebrafish embryos to electronic cigarette vapor. METHODS: Vapor was produced from a second-generation style vape pen and was incorporated into dechlorinated water at 0.6, 12, and 25 puffs/L, where one puff equals 55 ml of vapor. Vapor infused water was distributed among flasks to which zebrafish embryos were added. Exposures lasted for 24 hours and cardiovascular videos were recorded. Videos were analyzed and end systolic volume, end diastolic volume, stroke volume, heart rate, cardiac output, red blood cell density, and arterial and venous blood vessel diameters were measured. RESULTS: Here, it was found that embryonic exposure to nicotine free, cinnamon, and not chocolate, flavored electronic cigarette vapor at 25 puffs/L significantly decreased all cardiovascular parameters measured, with the exception of blood vessel diameter. No significant effect on any measured parameter was observed at 0.6 or 12 puffs/L with either flavor. CONCLUSION: These results indicate that cinnamon flavored electronic cigarette vapor can affect cardiovascular function during early development, even in the absence of nicotine, particularly at elevated exposure concentrations.
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Cigarrillo Electrónico a Vapor , Sistemas Electrónicos de Liberación de Nicotina , Animales , Cinnamomum zeylanicum , Cigarrillo Electrónico a Vapor/efectos adversos , Nicotina , Pez CebraRESUMEN
Cigarette smoke has been identified as a major risk factor for the development of age-related macular degeneration (AMD). As an alternative to conventional cigarettes (C-cigarette), electronic cigarettes (E-cigarette) have been globally promoted and are currently widely used. The increasing usage of E-cigarettes raises concerns with regard to short- (2 weeks), medium- (3 months), and long- (8 months) term consequences related to retinal tissue. In this report, a controlled study in mouse models was conducted to probe the comprehensive effects of E-cigarette vapor on retina, retinal pigmented epithelium (RPE), and choroidal tissues by (1) comparing the effects of C-cigarette smoke and E-cigarette vapor on retina separately and (2) determining the effects of E-cigarette vapor on the RPE and analyzing the changes with regard to inflammatory (IL-1ß, TNFα, iNOS) and angiogenic (VEGF, PEDF) mediators in retina/RPE/choroid by ELISA assays. The data showed that C-cigarette smoke exposure promoted an inflammatory reaction in the retina in vivo. Mice exposed to E-cigarette (nicotine-free) vapor developed inflammatory and angiogenic reactions more pronounced in RPE and choroid as compared to retinal tissue, while nicotine-containing E-cigarette vapor caused even a more serious reaction. Both inflammatory and pro-angiogenic reactions increased with the extension of exposure time. These results demonstrate that exposure to C-cigarette smoke is harmful to the retina. Likewise, the exposure to E-cigarette vapor (with or without nicotine) increases the occurrence and progression of inflammatory and angiogenic stimuli in the retina, which might also be related to the onset of wet AMD in humans. KEY MESSAGES: C-cigarette smoke exposure promotes an inflammatory reaction in the retina in vivo. Mice exposed to E-cigarette (nicotine-free) vapor develop inflammatory and angiogenic reactions more pronounced in RPE and choroid compared to retinal tissue, while nicotine-containing E-cigarette vapor causes even a more serious reaction. Both inflammatory and pro-angiogenic reactions increase with the extension of E-cigarette vapor exposure time.
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Cigarrillo Electrónico a Vapor/efectos adversos , Inflamación/inducido químicamente , Nicotiana/efectos adversos , Retina/efectos de los fármacos , Retina/patología , Humo/efectos adversos , Contaminación por Humo de Tabaco/efectos adversos , Animales , Sistemas Electrónicos de Liberación de Nicotina , Inflamación/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Modelos Animales , Nicotina/efectos adversos , Epitelio Pigmentado de la Retina/efectos de los fármacos , Epitelio Pigmentado de la Retina/patología , Fumar/efectos adversosRESUMEN
BACKGROUND: The blood-brain barrier (BBB) plays a critical role in protecting the central nervous system (CNS) from blood-borne agents and potentially harmful xenobiotics. Our group's previous data has shown that tobacco smoke (TS) and electronic cigarettes (EC) affect the BBB integrity, increase stroke incidence, and are considered a risk factor for multiple CNS disorders. Metformin was also found to abrogate the adverse effects of TS and EC. METHODS: We used sucrose and mannitol as paracellular markers to quantitatively assess TS and EC's impact on the BBB in-vitro. Specifically, we used a quantitative platform to determine the harmful effects of smoking on the BBB and study the protective effect of metformin. Using a transwell system and iPSCs-derived BMECs, we assessed TS and EC's effect on sucrose and mannitol permeability with and without metformin pre-treatment at different time points. Concurrently, using immunofluorescence (IF) and Western blot (WB) techniques, we evaluated the expression and distribution of tight junction proteins, including ZO-1, occludin, and claudin-5. RESULTS: Our data showed that TS and EC negatively affect sucrose and mannitol permeability starting after 6 h and up to 24 h. The loss of barrier integrity was associated with a reduction of TEER values. While the overall expression level of ZO-1 and occludin was not significantly downregulated, the distribution of ZO-1 was altered, and discontinuation patterns were evident through IF imaging. In contrast to occludin, claudin-5 expression was significantly decreased by TS and EC, as demonstrated by WB and IF data. CONCLUSION: In agreement with previous studies, our data showed the metformin could counteract the negative impact of TS and EC on BBB integrity, thus suggesting the possibility of repurposing this drug to afford cerebrovascular protection.
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Barrera Hematoencefálica/metabolismo , Cigarrillo Electrónico a Vapor/efectos adversos , Metformina/administración & dosificación , Neuroprotección/efectos de los fármacos , Humo/efectos adversos , Uniones Estrechas/metabolismo , Productos de Tabaco , Barrera Hematoencefálica/efectos de los fármacos , Permeabilidad Capilar/efectos de los fármacos , Permeabilidad Capilar/fisiología , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Claudina-5/metabolismo , Evaluación Preclínica de Medicamentos/métodos , Cigarrillo Electrónico a Vapor/administración & dosificación , Humanos , Células Madre Pluripotentes Inducidas/efectos de los fármacos , Células Madre Pluripotentes Inducidas/metabolismo , Neuroprotección/fisiología , Ocludina/metabolismo , Uniones Estrechas/efectos de los fármacos , Proteína de la Zonula Occludens-1/metabolismoRESUMEN
BACKGROUND: Lipid-laden macrophages detected by Oil-Red-O (ORO) stain in fresh bronchoalveolar lavage (BAL) specimens have been proposed as a potential diagnostic marker for E-cigarettes or vaping product use-associated lung injury (EVALI). However, studies are few, and the sensitivity and specificity of the test have not been thoroughly investigated. METHODS: We performed ORO stain on fresh BAL specimens from six confirmed EVALI and 36 non-EVALI patients. After semi-quantitative analysis, the sensitivity and specificity of ORO-positive macrophages (OPM) for detection of EVALI were calculated. RESULTS: No significant difference in cytomorphology or raw macrophage count was observed between EVALI and non-EVALI groups (49% vs 55% of all nucleated cells). However, with ORO stain, all EVALI specimens (6/6) showed a high percentage (≥50% of all macrophages) of OPM (mean 87%), and large (≥25% of host macrophage nuclear size) lipid droplets (mean 42%), while the majority of non-EVALI specimens showed a low percentage of OPM (32/36, mean 10%), and small lipid droplets (34/36, mean 6%). The differences between the two groups in both high OPM and large lipid droplet rates are statistically significant (P < .0001 for both comparisons). The combined sensitivity and specificity of high OPM and large lipid droplets for diagnosing EVALI were 100% and 94%, respectively. CONCLUSION: In BAL specimens obtained from patients with clinically suspected EVALI, a high percentage of OPM with large lipid droplets showed high sensitivity and specificity for the diagnosis of EVALI and may serve as a potentially useful tool in the evaluation of vaping-related lung injury, improving diagnostic accuracy.
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Compuestos Azo , Lesión Pulmonar/diagnóstico , Lesión Pulmonar/etiología , Macrófagos/metabolismo , Vapeo/efectos adversos , Adolescente , Adulto , Líquido del Lavado Bronquioalveolar/citología , Colorantes , Cigarrillo Electrónico a Vapor/efectos adversos , Sistemas Electrónicos de Liberación de Nicotina , Femenino , Humanos , Masculino , Sensibilidad y Especificidad , Coloración y Etiquetado/métodos , Adulto JovenRESUMEN
The COVID-19 pandemic has affected over 114 million people and has resulted in >2.5 million deaths so far. Some people have greater susceptibility which influences both SARS-CoV-2 infectivity and COVID-19 severity. Smoking is associated with increased ACE-2, the receptor for SARS-CoV-2, which facilitates its entry through the lung. However, despite the widespread use of e-cigarettes, also known as 'vaping', little is known regarding the effects of vaping on ACE-2 expression and how this affects SARS-CoV-2 infection. In addition, the added effect of nicotine in the vapor is also unknown. Thus, we tested whether vaping induces ACE-2 expression in the mouse lung. BALB/c mice exposed to e-cigarette vapor (±nicotine) resulted in a significant increase in peribronchiolar inflammation and influx of immune cells into the airways. Vapor increased monocyte chemoattractant protein-1, interleukin 1ß, and KC levels in bronchoalveolar lavage fluid in both sexes, which were further enhanced by nicotine (whereas increase in interleukin 6 was sex and nicotine independent). The reduction in basal inspiratory capacity with vapor exposure occurred independent of sex or nicotine. The increase in methacholine-induced airway hyper-responsiveness was independent of sex; however, in female mice it was only significant in the nicotine-exposed group. Lung ACE-2 expression was increased in male mice in a nicotine-dependent manner as compared with female mice. Collectively, while vaping (±nicotine) induced airway inflammation and impaired lung function, the induction of lung ACE-2 occurred to a significantly greater degree in males exposed to vapor containing nicotine as compared with females. Thus, via these effects on ACE-2 expression in the lungs and airways, vaping itself may facilitate SARS-CoV-2 entry into the airways.
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Enzima Convertidora de Angiotensina 2/metabolismo , COVID-19/etiología , Cigarrillo Electrónico a Vapor/efectos adversos , Pulmón/metabolismo , Animales , Líquido del Lavado Bronquioalveolar/química , Quimiocina CCL2/metabolismo , Modelos Animales de Enfermedad , Femenino , Humanos , Interleucina-1beta/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Nicotina/efectos adversos , Factores de Riesgo , Factores Sexuales , Vapeo/efectos adversosRESUMEN
Nicotine addiction is a severe public health problem. The aim of this study was to investigate the alterations in key neurotransmissions after 60 days of withdrawal from seven weeks of intermittent cigarette smoke, e-cigarette vapours, or an e-cigarette vehicle. In the nicotine withdrawal groups, increased depressive and anxiety/obsessive-compulsive-like behaviours were demonstrated in the tail suspension, sucrose preference and marble burying tests. Cognitive impairments were detected in the spatial object recognition test. A significant increase in Corticotropin-releasing factor (Crf) and Crf1 mRNA levels was observed, specifically after cigarette withdrawal in the caudate-putamen nucleus (CPu). The nociceptin precursor levels were reduced by cigarette (80%) and e-cigarette (50%) withdrawal in the CPu. The delta opioid receptor showed a significant reduction in the hippocampus driven by the exposure to an e-cigarette solubilisation vehicle, while the mRNA levels doubled in the CPu of mice that had been exposed to e-cigarettes. Withdrawal after exposure to e-cigarette vapour induced a 35% Bdnf mRNA decrease in the hippocampus, whereas Bdnf was augmented by 118% by cigarette withdrawal in the CPu. This study shows that long-term withdrawal-induced affective and cognitive symptoms associated to lasting molecular alterations in peptidergic signalling may determine the impaired neuroplasticity in the hippocampal and striatal circuitry.
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Cigarrillo Electrónico a Vapor/efectos adversos , Hipocampo/efectos de los fármacos , ARN Mensajero/genética , Síndrome de Abstinencia a Sustancias/genética , Contaminación por Humo de Tabaco/efectos adversos , Animales , Factor Neurotrófico Derivado del Encéfalo/genética , Núcleo Caudado/efectos de los fármacos , Núcleo Caudado/metabolismo , Núcleo Caudado/fisiopatología , Hormona Liberadora de Corticotropina/genética , Regulación hacia Abajo/efectos de los fármacos , Hipocampo/metabolismo , Hipocampo/fisiopatología , Masculino , Ratones , Ratones Endogámicos BALB C , Péptidos Opioides/genética , Orexinas/genética , Putamen/efectos de los fármacos , Putamen/metabolismo , Putamen/fisiopatología , Receptores de Hormona Liberadora de Corticotropina/genética , Receptores Opioides/genética , Síndrome de Abstinencia a Sustancias/etiología , Síndrome de Abstinencia a Sustancias/fisiopatología , Regulación hacia Arriba/efectos de los fármacosRESUMEN
Health risk associated with the use of combustible cigarettes is well characterized and numerous epidemiological studies have been published for many years. Since more than a decade, innovative non-combusted tobacco products have emerged like heated tobacco products (HTP) or electronic cigarettes (EC). Long-term effects of these new products on health remain, however, unknown and there is a need to characterize associated potential health risks. The time dedicated to epidemiological data generation (at least 20 to 40 years for cancer endpoint), though, is not compatible with innovative development. Surrogates need, therefore, to be developed. In this work, non-cancer and cancer risks were estimated in a range of HTP and commercial combustible cigarettes based upon their harmful and potentially harmful constituent yields in aerosols and smoke, respectively. It appears that mean lifetime cancer risk values were decreased by more than one order of magnitude when comparing HTPs and commercial cigarettes, and significantly higher margin of exposure for non-cancer risk was observed for HTPs when compared to commercial cigarettes. The same approach was applied to two commercial ECs. Similar results were also found for this category of products. Despite uncertainties related to the factors used for the calculations and methodological limitations, this approach is valuable to estimate health risks associated to the use of innovative products. Moreover, it acts as predictive tool in absence of long-term epidemiological data. Furthermore, both cancer and non-cancer risks estimated for HTPs and ECs highlight the potential of reduced risk for non-combusted products when compared to cigarette smoking.
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Fumar Cigarrillos/efectos adversos , Cigarrillo Electrónico a Vapor/efectos adversos , Sistemas Electrónicos de Liberación de Nicotina , Neoplasias/epidemiología , Productos de Tabaco/efectos adversos , Vapeo/efectos adversos , Aerosoles , Humanos , Exposición por Inhalación , Neoplasias/diagnóstico , Medición de Riesgo , Factores de RiesgoRESUMEN
A history of chronic cigarette smoking is known to increase risk for acute respiratory distress syndrome (ARDS), but the corresponding risks associated with chronic e-cigarette use are largely unknown. The chromosomal fragile site gene, WWOX, is highly susceptible to genotoxic stress from environmental exposures and thus an interesting candidate gene for the study of exposure-related lung disease. Lungs harvested from current versus former/never-smokers exhibited a 47% decrease in WWOX mRNA levels. Exposure to nicotine-containing e-cigarette vapor resulted in an average 57% decrease in WWOX mRNA levels relative to vehicle-treated controls. In separate studies, endothelial (EC)-specific WWOX knockout (KO) versus WWOX flox control mice were examined under ARDS-producing conditions. EC WWOX KO mice exhibited significantly greater levels of vascular leak and histologic lung injury. ECs were isolated from digested lungs of untreated EC WWOX KO mice using sorting by flow cytometry for CD31+ CD45-cells. These were grown in culture, confirmed to be WWOX deficient by RT-PCR and Western blotting, and analyzed by electric cell impedance sensing as well as an FITC dextran transwell assay for their barrier properties during methicillin-resistant Staphylococcus aureus or LPS exposure. WWOX KO ECs demonstrated significantly greater declines in barrier function relative to cells from WWOX flox controls during either methicillin-resistant S. aureus or LPS treatment as measured by both electric cell impedance sensing and the transwell assay. The increased risk for ARDS observed in chronic smokers may be mechanistically linked, at least in part, to lung WWOX downregulation, and this phenomenon may also manifest in the near future in chronic users of e-cigarettes.
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Fumar Cigarrillos/efectos adversos , Regulación hacia Abajo/efectos de los fármacos , Cigarrillo Electrónico a Vapor/efectos adversos , Pulmón/efectos de los fármacos , Nicotina/efectos adversos , Síndrome de Dificultad Respiratoria/inducido químicamente , Oxidorreductasa que Contiene Dominios WW/metabolismo , Animales , Humanos , Pulmón/metabolismo , Masculino , Staphylococcus aureus Resistente a Meticilina/patogenicidad , Ratones , Ratones Endogámicos C57BL , Síndrome de Dificultad Respiratoria/metabolismo , Infecciones Estafilocócicas/metabolismo , Nicotiana/efectos adversos , Productos de Tabaco/efectos adversosRESUMEN
Using electronic cigarette (e-cig) among youth is becoming a critical public health crisis in the USA. However, the biological impacts of the e-cig on multiple organ systems, especially in the cardiovascular system, are largely unknown. Unlike conventional tobacco, e-cig combines various chemical ingredients including nicotine and other add-on non-nicotine chemicals, such as the solvents (propylene glycol and/or vegetable glycerin) and flavoring chemicals, which dramatically increases the diversity of the potential implications. The recent outbreak of e-cig vaping-related tragic deaths in youth and multiple hospitalized patients raised a question on the safety of e-cig use and led to an urgent need for the knowledge of the health risk of the e-cig compositions. Therefore, in the review, we summarized the latest findings from both human and animal studies on the potential cardiovascular toxicological effects of e-cig on the cardiovascular system in terms of the systemic physiological implications and the cellular and molecular mechanisms involved.