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.

电子烟或雾化产品使用相关肺损伤 (EVALI) 是一种急性呼吸衰竭综合征，其特征是单核细胞和中性粒细胞肺泡炎症。流行病学和临床证据表明，维生素 E 醋酸盐 (VEA) 在 EVALI 的发展中发挥作用，但尚不清楚 VEA 是否具有直接的肺毒性。为了验证雾化 VEA 会导致小鼠肺损伤并直接伤害人类肺泡上皮细胞的假设，我们将成年小鼠和原代人类肺泡上皮 II 型 (AT II) 细胞暴露于由专为电子烟油设计的装置产生的 VEA 气雾剂中。小鼠的结果测量包括肺水肿、BAL 分析、组织学和炎性细胞因子；体外结果包括细胞死亡、细胞因子释放、VEA 的细胞摄取和基因表达分析。两种模型的比较暴露包括流行的含尼古丁的 JUUL 气雾剂。我们发现，与对照组和 JUUL 暴露小鼠相比，VEA 导致肺水和 BAL 蛋白的剂量依赖性增加，并与 BAL 中性粒细胞、载油巨噬细胞、多核巨细胞和炎性细胞因子增加有关。VEA 气雾剂对 AT II 细胞也有毒性，导致细胞死亡增加以及单核细胞和中性粒细胞趋化因子的释放。VEA 被 AT II 细胞直接吸收，导致几种炎症生物学途径的差异基因表达。鉴于 EVALI 爆发的流行病学和临床特征，这些结果表明 VEA 起着重要的因果作用。