Altered lung function in mice is a sensitive indicator of lung damage following 6 months of electronic nicotine...

With the rising prevalence of vaping, there is a pressing need to identify biomarkers of toxicity related to chronic effects induced by the inhalation of electronic nicotine delivery system (ENDS) aerosols. In a mouse model, we investigated the long-term pulmonary effects associated with exposures to cinnamon-flavored ENDS aerosols for up to 6 mo. Following exposures and after 2 mo of recovery, pulmonary function testing and lung biochemical responses were assessed. Despite similar serum cotinine concentrations in male and female mice, males exposed for 6 mo to ENDS aerosols exhibited significant reductions in tidal and minute volumes, breathing frequency, and elevated respiratory elastance, while significantly increased tissue damping and respiratory resistance were observed in both sexes. All parameters, except minute volume and breathing frequency in males, returned to baseline following recovery. Although there were no significant changes in pulmonary inflammation in all groups, lung RNA sequencing revealed significant upregulation of Cxcl5, a neutrophil chemotactic chemokine, in all groups exposed to ENDS aerosols. In total, 69 genes in males and 63 genes in females, were dysregulated, including upregulated proinflammatory and oxidative stress-related genes. HIF-1α in lung tissue, and CXCL5 serum concentrations, were significantly elevated in the ENDS and recovery groups, respectively, compared with controls. Overall, this study showed that pulmonary inflammation is not a hallmark of long-term ENDS aerosol exposure, whereas altered lung function is a sensitive indicator of lung damage in mice.NEW & NOTEWORTHY In mice, inhalation of cinnamon-flavored electronic nicotine delivery system (ENDS) aerosols for 6 mo induced pulmonary effects, including hypoxia and molecular changes. Our data suggest that hypoxia may be linked to lung function deterioration, independent of pulmonary inflammation. Overall, our findings indicate that altered lung structure and function, rather than pulmonary inflammation, are sensitive indicators of lung damage in mice chronically exposed to ENDS aerosols.