Electronic Nicotine Delivery System Aerosol-induced Cell Death and Dysfunction in Macrophages and Lung Epithelial Cells

Abstract

Electronic nicotine delivery system (ENDS) use is outpacing our understanding of its potential harmful effects. Homeostasis of the lung is maintained through proper balance of cell death, efferocytic clearance, and phagocytosis of pathogens. To investigate whether ENDS use has the potential to alter this balance, we developed physiologically relevant ENDS exposure paradigms for lung epithelial cells and primary macrophages. In our studies, cells were exposed directly to aerosol made from carefully controlled components with and without nicotine. We found that ENDS aerosol exposure led to apoptosis, secondary necrosis, and necrosis in lung epithelial cell models. In contrast, macrophages died mostly by apoptosis and inflammatory caspase-mediated cell death when exposed to ENDS aerosol. The clearance of dead cells and pathogens by efferocytosis and phagocytosis, respectively, is an important process in maintaining a healthy lung. To investigate the impact of ENDS aerosol on macrophage function independent of general toxicity, we used an exposure time that did not induce cell death in primary macrophages. Exposure to ENDS aerosol containing nicotine inhibited nearly all phagocytic and greatly reduced the efferocytic abilities of primary macrophages. When challenged with a bacterial pathogen, there was decreased bacterial clearance. The presence of nicotine in the ENDS aerosol increased its toxicity and functional impact; however, nicotine exposure alone did not have any deleterious effects. These data demonstrate that ENDS aerosol exposure could lead to increased epithelial cell and macrophage death in the lung and impair important macrophage functions that are essential for maintenance of lung function.

Electronic Cigarette Aerosol Is Cytotoxic and Increases ACE2 Expression on Human Airway Epithelial Cells: Implications for SARS-CoV-2 (COVID-19)

“…Previously, programmed cell death has been shown in BEAS-2B cells and macrophages following 24 h exposure to unflavored ENDS aerosol (PG/VG ± nicotine) [ 34 ]. In our study, treatment with PG/VG ± nicotine causes a reduction in viability, and PG/VG with nicotine causes cell membrane disruption and an increase in LDH release.…”

Cardiorespiratory and Immunologic Effects of Electronic Cigarettes

“…Stimulation of cytokine production in macrophages by e-cigarette exposure is accompanied by a decrease in their phagocytic activity. Exposure of macrophages to e-cigarette aerosol condensate has been reported to result in a 50-fold increase in ROS production and a significant inhibition of phagocytosis [ 83 ], efferocytosis, and bacterial clearance [ 89 ], and exposing THP-1 macrophages to e-cigarette aerosol extracts has been shown to decrease the intracellular burden of Mycobacterium tuberculosis [ 90 ]. Similarly, when exposed to freshly generated e-cigarette aerosol at the air-liquid interface, alveolar macrophages and neutrophils show reduced anti-microbial activity against Staphylococcus aureus [ 91 ].…”

Current Perspectives on Characteristics, Compositions, and Toxicological Effects of E-Cigarettes Containing Tobacco and Menthol/Mint Flavors

“…In an additional study into the effects of exposure to general vapor from ENDS, damage to both lung epithelial cells and macrophages was noted. Following exposure, increased apoptosis and necrosis of the epithelial cells was observed, as well as increased cell death in the macrophages (Serpa et al, 2020).…”