Dose-Dependent Pulmonary Toxicity of Aerosolized Vitamin E Acetate

Am J Respir Cell Mol Biol. 2020 Dec;63(6):748-757. doi: 10.1165/rcmb.2020-0209OC.


Electronic-cigarette, or vaping, product use-associated lung injury (EVALI) is a syndrome of acute respiratory failure characterized by monocytic and neutrophilic alveolar inflammation. Epidemiological and clinical evidence suggests a role of vitamin E acetate (VEA) in the development of EVALI, yet it remains unclear whether VEA has direct pulmonary toxicity. To test the hypotheses that aerosolized VEA causes lung injury in mice and directly injures human alveolar epithelial cells, we exposed adult mice and primary human alveolar epithelial type II (AT II) cells to an aerosol of VEA generated by a device designed for vaping oils. Outcome measures in mice included lung edema, BAL analysis, histology, and inflammatory cytokines; in vitro outcomes included cell death, cytokine release, cellular uptake of VEA, and gene-expression analysis. Comparison exposures in both models included the popular nicotine-containing JUUL aerosol. We discovered that VEA caused dose-dependent increases in lung water and BAL protein compared with control and JUUL-exposed mice in association with increased BAL neutrophils, oil-laden macrophages, multinucleated giant cells, and inflammatory cytokines. VEA aerosol was also toxic to AT II cells, causing increased cell death and the release of monocyte and neutrophil chemokines. VEA was directly absorbed by AT II cells, resulting in the differential gene expression of several inflammatory biological pathways. Given the epidemiological and clinical characteristics of the EVALI outbreak, these results suggest that VEA plays an important causal role.

Keywords: E-cigarette or vaping product use–associated lung injury; acute respiratory distress syndrome; pulmonary edema; vitamin E acetate.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Acetates / pharmacology*
  • Animals
  • Electronic Nicotine Delivery Systems
  • Humans
  • Lung / drug effects*
  • Lung / pathology
  • Lung Injury / chemically induced
  • Lung Injury / drug therapy*
  • Lung Injury / pathology
  • Mice, Inbred C57BL
  • Nicotine / pharmacology
  • Vaping
  • Vitamin E / analysis
  • Vitamin E / pharmacology*


  • Acetates
  • Vitamin E
  • Nicotine