E-cigarette Vaping Accelerates Aging of the Lower Respiratory Tract in Mice in a Sex-dependent Manner

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Abstract Rationale: Aging leads to changes in gene expression, including increased expression of inflammatory, DNA damage, and innate immunity genes, and decreased expression of wound healing and lipid metabolism genes. Further, some transcriptomic age-related changes are adaptive while others are maladaptive. Overall, aging of the lungs is associated with declining respiratory and immunologic function and increased development and progression of disease. While cigarette smoking is known to accelerate lung aging, it is unknown whether newer tobacco products, such as e-cigarettes, promote lung aging. Here we sought to define effects of vaping on the lung transcriptome related to aging and associated biological pathways. Because our previous work identified numerous gene expression, protein level, and cellular changes in the lungs due to e-cigarette use, we hypothesized that long term exposure to e-cigarettes would cause accelerated lung aging in mice. Methods: Male and female C57BL/6, 6-8 week-old mice were exposed to e-cigarette aerosols (70:30 propylene glycol/glycerol (PG/Gly) + 59mg/mL nicotinic salts (E-cig), 70:30 PG/Gly (Vehicle), Mango- or Mint-flavored JUUL) or room air (control) through a whole-body exposure system (inExpose; SciReq) for 1 hour/day, 5 days/week, for 3 months. Pulmonary arteries were flushed with PBS, lungs were harvested, RNA isolated and RNAseq conducted. An unbiased differential gene expression analysis was performed by comparing each group to air controls within their respective sex groups. Aged-related genes were then selected for biological pathway analysis to identify significantly enriched pathways. Results: E-cigarette and no nicotine (vehicle) aerosol exposures induced similar changes in age-related gene expression in the lung. We identified sex differences, with female mice exhibiting fewer age-related gene expression changes compared to males. Most aging signatures in the flavored e-cigarette exposed mice (Mint and Mango) were expressed in the opposite direction observed with aging, with most genes being downregulated. The antigen processing and presentation and actin cytoskeleton pathways were enriched with genes such as CTSS and ITGAX in male e-cigarette, male vehicle, and female flavored e-cigarette cohorts. The leukocyte transendothelial migration pathway was enriched with genes such as CYBB in both the female flavored and male e-cigarette cohorts. Conclusions: These data demonstrate that chronic inhalation of e-cigarettes aerosols may accelerate lung aging, in a sex-dependent manner. PG and Gly are the primary chemicals within e-cigarette vapor driving gene dysregulation. However, flavorant chemicals may also have harmful effects on age-protective genes. More work is needed to define the underlying mechanisms by which e-cigarettes accelerate lung aging.

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