E-cigarette use has increased substantially, particularly among adolescents and young adults, yet its long-term respiratory effects remain incompletely understood. E-cigarette aerosol contains biologically active constituents, including nicotine, propylene glycol, vegetable glycerin, flavoring chemicals, aldehydes, metals, particles, and reactive oxygen species, which may disrupt respiratory epithelial homeostasis. This review synthesizes experimental, preclinical, and human-relevant evidence linking e-cigarette aerosol exposure to respiratory epithelial injury, with emphasis on ferroptosis-related mechanisms. Available evidence indicates that e-cigarette aerosol can impair epithelial barrier integrity, alter mucociliary defense, increase MUC5AC expression, induce oxidative stress, and promote inflammatory signaling. Emerging preclinical data suggest that electronic nicotine delivery system exposure may induce ferroptosis-associated lung injury through increased CD71/TFR1 and ACSL4 expression, reduced GPX4, altered lipid profiles, BODIPY-C11-positive lipid peroxidation, epithelial cell death, inflammation, mucus accumulation, emphysema-like pathology, and fibrosis. Mechanistically, e-cigarette aerosol may create a ferroptosis-permissive epithelial environment by promoting redox imbalance, GPX4/GSH/SLC7A11 antioxidant defense impairment, altered iron handling, ACSL4-mediated PUFA-phospholipid remodeling, NRF2/ARE stress responses, mitochondrial dysfunction, and lipid peroxide accumulation. Ferroptotic epithelial injury may further amplify airway inflammation and remodeling through DAMP release, macrophage recruitment, cytokine production, barrier disruption, mucus dysregulation, and extracellular matrix deposition. However, direct human evidence remains limited, and many mechanistic links are extrapolated from cigarette smoke, particulate matter, and broader lung injury models. Future studies should use standardized exposure systems, human-relevant airway and alveolar models, comprehensive ferroptosis markers, and ferroptosis-specific rescue experiments to determine whether ferroptosis is a driver, amplifier, or downstream marker of e-cigarette-associated respiratory injury.
Understanding the fundamental processes involved in repairing the airway wall following injury is fundamental to understanding the way in which these processes are perturbed during disease pathology. Indeed complex diseases such as asthma and chronic obstructive pulmonary disease (COPD) have at their core evidence of airway wall remodeling processes that play a crucial functional role in these diseases. The authors sought to understand the dynamic cellular events that occur during bronchial airway epithelial repair in sheep. The injury was induced by endobronchial brush biopsy (BBr), a process that causes epithelial débridement and induces a consequential repair process. In addition, the current experimental protocol allowed for the time-dependent changes in airway wall morphology to be studied both within and between animals. The initial débridement was followed by evidence of dedifferentiation in the intact epithelium at the wound margins, followed by proliferation of cells both within the epithelium and in the deeper wall structures, notably in association with the submucosal glands and smooth muscle bundles. Seven days after injury, although the airway wall was thickened at the site of damage, the epithelial layer was intact, with evidence of redifferentiation. These studies, in demonstrating broad agreement with previous studies in small animals, indicate the wider relevance of this system as a comparative model and should provide a solid basis upon which to further characterize the critical cellular and molecular interactions that underlie both effective restitution and pathological repair.