Vitamin E acetate and its aerosol activate aryl hydrocarbon receptor signaling and exacerbate inflammation in human U937-derived macrophages

In 2019, a number of patients were hospitalized after the use of electronic cigarettes and displayed acute lung injuries. Such injury was categorized as e-cigarette or vaping associated lung injury (EVALI). Among these patients, Vitamin E acetate (VEA) was detected in most used electronic cigarette cartridges as well as the patients' bronchoalveolar lavage fluid, suggesting VEA to be a culprit of causing lung injury. Although further experiments verified the potential of VEA aerosol to cause cytotoxicity and lung injury, mechanisms of VEA aerosol toxicity are not well understood. In this study, we tested the toxicity of VEA, and its aerosol using a human macrophage model. VEA aerosols significantly induced oxidative stress as well as proinflammatory responses. In addition, the aerosol activated the aryl hydrocarbon receptor (AhR) signaling pathway, inducing CYP1A1 expression in human U937 monocyte-derived macrophages. Additionally, non-aerosolized VEA and VEA aerosol induce the expression of inflammatory markers such as interleukin (IL)-8 and cyclooxygenase (COX)-2 in an AhR-dependent manner as shown in CRISPR-cas9 AhR-knockout U937-derived human macrophages. These results suggest that VEA is an agonist for AhR and provide new potential mechanisms for lung injury induced by VEA aerosol inhalation via AhR activation in addition to the generation of oxidative stress.