Biological sex modulates lung injury severity in adolescent mice exposed to short‐term aerosolized vitamin E acetate

The E-cigarette or Vaping product-Associated Lung Injury (EVALI) causes severe acute respiratory failure and, in some cases, death. Most cases are linked to tetrahydrocannabinol-containing e-cigarette products adulterated with vitamin E acetate. Despite regulation and awareness efforts, VEA persists in biological samples from EVALI patients and remains a public health concern, particularly among adolescent males. The mechanisms driving VEA-induced lung injury, and how they may be differentiated by sex, remain poorly understood. To address this, age- and size-matched adolescent male and female mice were exposed to aerosolized VEA for 3 or 10 days. By Day 10, VEA exposure caused histopathologic lung injury and systemic inflammation, with alveolar barrier dysfunction evident on Day 3. Male mice developed more severe injury and immune dysregulation, with elevated lung interleukin-1β, interleukin-6, and keratinocyte chemoattractant and reduced expression of club cell secretory protein along the airway epithelium. Female mice showed higher serum levels of soluble receptor for advanced glycation end products, a biomarker of alveolar injury and inflammation that also functions as an immune modulator. This is the first study to identify sex-specific differences in pulmonary responses to VEA exposure. These findings offer insight into EVALI immunopathogenesis and may explain population-level sex disparities in disease severity.