Dose-Dependent Pulmonary Toxicity of Aerosolized Vitamin E Acetate
Dose-Dependent Pulmonary Toxicity of Aerosolized Vitamin E Acetate
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DOI：
10.1165/rcmb.2020-0209oc
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发表时间：
2020-12-01
影响因子：
6.4
通讯作者：
Gotts, Jeffrey E.
中科院分区：
文献类型：
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作者：
Matsumoto, Shotaro;Fang, Xiaohui;Gotts, Jeffrey E.
电子烟或vaping产品使用相关性肺损伤（EVALI）是一种急性呼吸衰竭综合征，其特征为单核细胞和嗜中性粒细胞肺泡炎症。流行病学和临床证据表明，维生素E醋酸酯（VEA）在EVALI的发展中发挥作用，但目前尚不清楚VEA是否具有直接的肺毒性。为了测试雾化VEA导致小鼠肺损伤并直接损伤人肺泡上皮细胞的假设，我们将成年小鼠和原代人肺泡上皮II型（AT II）细胞暴露于由设计用于雾化油的装置产生的VEA气溶胶。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蛋白呈剂量依赖性增加，并与BAL中性粒细胞、含油巨噬细胞、多核巨细胞和炎症细胞因子增加相关。VEA气溶胶对AT H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暴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。
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 H 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.