Biology subjects

Muthumalage, T.

Publications and source records attributed to Muthumalage, T..

4 recordsLinked to original sources

bioRxiv2025

Comparative toxicity of menthol- and tobacco-flavored electronic cigarette constituents causing inflammation, epithelial barrier dysfunction, and nicotinic acetylcholine receptor modulation in the absence of nicotine.

BackgroundMenthol and tobacco-flavored nicotine delivery systems (ENDS) are widely used as safer alternatives to combustible cigarettes. These flavored products include constituents such as propylene glycol/vegetable glycerin (PG/VG), benzoic acid, acetoin, L-menthone, 98% menthone, 2-isopropyl-N,2,3-trimethylbutanamide (WS-23), vanillin, and carvone. However, little is known about the potential adverse effects of the constituents in these flavored products. Rationale and hypothesisWe hypothesized that exposure to common constituents in tobacco- and menthol-flavored ENDS constituents could elicit a lung-injurious response mediated by nicotinic acetylcholine receptor (-nAChR or CHRNA) modulation. MethodsHuman bronchial epithelial cells, BEAS-2B, cells were treated with commonly used menthol and tobacco constituents on trans well inserts. Transepithelial barrier resistance (TEER) and millivolts (mV) across epithelial cells were measured over a 24-hour time. To assess the elicited inflammatory response, cytokines IL8 and IL6 were quantified in the conditioned media. Cytotoxicity caused by these constituents was evaluated by acridine orange/propidium iodide (AO/PI) staining of the cells after 24 hrs. alpha nicotinic receptor protein abundance (1, 4, 5, and 7) was quantified by immunoblotting. ResultsEpithelial integrity was decreased over time with a significant decrease in TEER and voltage by ENDS constituents. A significant increase in IL6 in conditioned media was observed in PG/VG, carvone, and WS-23 treated cells. Carvone-treated cells also elicited significantly elevated IL8 in conditioned media. Further, increased 1, 4, 5, and 7 nAChR were seen in cells treated with PG/VG, Acetoin, Carvone, and WS-23. ConclusionThese findings suggested that common constituents in menthol- and tobacco-flavored ENDS induce lung inflammation, epithelial barrier dysfunction, and lung injury. Further, our data implicate potential lung disease pathogenesis via nAChR modulation-mediated inflammation by exposure to these ENDS constituents, even in the absence of nicotine.

pharmacology and toxicology↗

bioRxiv2022

Nose-only Exposure to Cherry and Tobacco Flavored E-cigarettes Induced Lung Inflammation in Mice in a Sex-dependent Manner

Flavoring chemicals utilized in electronic nicotine delivery systems (ENDS) have been shown to result in an increase in cellular inflammation, meanwhile, the effects of fruit and tobacco flavors on lung inflammation by nose-only exposures to mice are relatively unknown. We hypothesized that C57BL/6J mice exposed to flavored e-cigarettes would result in an increase in lung inflammation. C57BL/6J mice were exposed to air, propylene glycol/vegetable glycerin (PG/VG), and e-liquids "Apple", "Cherry", "Strawberry", "Wintergreen", and "Smooth & Mild Tobacco", for one hour per day for a three day exposure. Quantification of flavoring chemicals was measured by proton nuclear magnetic resonance spectroscopy (1H NMR), differential cell counts by flow cytometry, pro-inflammatory cytokines/chemokines by ELISA, and matrix metalloproteinase levels by western blot. Exposure to PG/VG, Apple, and Smooth & Mild Tobacco resulted in an increase in neutrophil cell count in lung bronchoalveolar lavage fluid (BALF). Strawberry exposure increased KC levels in BALF while in lung homogenate KC levels were increased in PG/VG, Cherry, and Smooth & Mild Tobacco exposure. Exposure to PG/VG and Cherry increased IL-6 levels and in all exposed mice there was a male-specific decrease in MCP-1 levels in lung homogenate. Mice exposed to PG/VG, Apple, Cherry, and Wintergreen resulted in an increase in MMP2 levels. Our results indicate that female mice exposed to cherry flavored e-liquids and male mice exposed to tobacco flavored e-liquids resulted in an increase in inflammation, while exposure to mint flavored e-liquids resulted in a decrease in inflammatory cytokine and an increase in tissue repair proteins. This study revealed that flavored-based e-cigarette exposure elicited sex-specific alterations in lung inflammation, with cherry flavors/benzaldehyde eliciting female-specific increases in inflammation. This highlights the toxicity of flavored chemicals and the further need for regulation of flavoring chemicals.

pharmacology and toxicology↗

bioRxiv2020

Pulmonary toxicity and inflammatory response of e-cigarettes containing medium-chain triglyceride oil and vitamin E acetate: Implications in the pathogenesis of EVALI but independent of SARS-COV-2 COVID-19 related proteins

Recently, there has been an outbreak associated with the use of e-cigarette or vaping products, associated lung injury (EVALI). The primary components of vaping products, vitamin E acetate (VEA) and medium-chain triglycerides (MCT) may be responsible for acute lung toxicity. Currently, little information is available on the physiological and biological effects of exposure to these products. We hypothesized that these e-cig cartridges and their constituents (VEA and MCT) induce pulmonary toxicity, mediated by oxidative damage and inflammatory responses, leading to acute lung injury. We studied the potential mechanisms of cartridge aerosol induced inflammatory response by evaluating the generation of reactive oxygen species by MCT, VEA, and cartridges, and their effects on the inflammatory state of pulmonary epithelium and immune cells both in vitro and in vivo. Cells exposed to these aerosols generated reactive oxygen species, caused cytotoxicity, induced epithelial barrier dysfunction, and elicited an inflammatory response. Using a murine model, the parameters of acute toxicity to aerosol inhalation were assessed. Infiltration of neutrophils and lymphocytes was accompanied by significant increases in IL-6, eotaxin, and G-CSF in the bronchoalveolar lavage fluid (BALF). In mouse plasma, eicosanoid inflammatory mediators, leukotrienes, were significantly increased. Plasma from e-cig users also showed increased levels of hydroxyeicosatetraenoic acid (HETEs) and various eicosanoids. Exposure to e-cig cartridge aerosols showed the most significant effects and toxicity compared to MCT and VEA. In addition, we determined at SARS-COV-2 related proteins and found no impact associated with aerosol exposures from these tested cartridges. Overall, this study demonstrates acute exposure to specific e-cig cartridges induces in vitro cytotoxicity, barrier dysfunction, and inflammation and in vivo mouse exposure induces acute inflammation with elevated pro-inflammatory markers in the pathogenesis of EVALI.Competing Interest StatementThe authors have declared no competing interest.View Full Text

pharmacology and toxicology↗

bioRxiv2020

Chemical constituents involved in e-cigarette, or vaping product use-associated lung injury (EVALI)

BackgroundThe Centers for Disease Control (CDC) declared e-cigarette (e-cig), or vaping product use-associated lung injury (EVALI) a national outbreak due to the high incidence of emergency department admissions and deaths. Investigators have identified vitamin E acetate (VEA) as the plausible cause for EVALI, based on compounds found in bronchoalveolar lavage fluid. ObjectivesWe defined the chemical constituents present in e-cig cartridges associated with EVALI and compared constituents to medical-grade and cannabidiol (CBD) containing cartridges. MethodsWe measured chemicals and elemental metals in e-liquid and vapor phases of e-cig counterfeit cartridges by Gas Chromatography (GC) and Mass Spectrometry (MS), EPA method TO-15 by GCMS, and ICP-MS analysis. ResultsWe have identified chemical constituents in e-cig vaping tetrahydrocannabinol (THC)-containing counterfeit cartridges compared to medical-grade and cannabidiol (CBD) containing cartridges. Apart from VEA and THC, other potential toxicants correlated with EVALI included solvent-derived hydrocarbons, silicon conjugated compounds, various terpenes, pesticides/plasticizers/polycaprolactones, and metals. These chemicals are known to cause symptoms, such as cough, shortness of breath or chest pain, nausea, vomiting or diarrhea, fatigue, fever, or weight loss, all symptoms presenting in patients with EVALI. ConclusionThis study provides insights into understanding the chemical-induced disease mechanism of acute lung injury.

pharmacology and toxicology↗