Admin Suppl to examine the role of Vit E Acetate in ENDS

电子烟在从不吸烟和经常吸烟的人中越来越受欢迎，他们被激烈的广告说服 宣传他们使用香烟作为香烟的健康替代品。加热后的汽化内容物是否在 电子烟，如丙二醇(PG)、植物甘油(VG)加或不加尼古丁，是安全的替代品 吸烟仍不为人所知。我们开发了一种健壮的常规暴露和等量免疫暴露的小鼠模型。 并做出了几项新的发现，为肺内ECG的毒理学提供了独特的见解。在 在我们资助的第一年，我们已经证明了流行的特定溶剂(例如PG/VG的60/40比例)是独立的 尼古丁，可改变肺脂平衡，破坏肺泡巨噬细胞和上皮细胞的功能 (Madison等人，JCI，2019年)。我们发现接触ECG会导致内源性脂肪含量增加。 通常存在于肺衬里液中，但与之相关的表面活性蛋白(SP)-A和SP-D 血脂显著降低。最近的几份报告描述了零星的ECG(尼古丁和/或 出现神秘(非传染性)类脂性肺炎的吸毒者。这些呼吸系统 疾病的临床特征是呼吸困难、疲劳，最严重的形式是呼吸衰竭和死亡。 目前，导致ECG使用者急性呼吸衰竭的病因(S)尚不清楚，但 FDA报告说，与住院患者有关的ECG液体样本中有超过1/2的维他命检测呈阳性 (维生素E)醋酸酯。在这份补充申请中，我们申请资金来检查急性和慢性影响 对吸入维生素E醋酸酯进行研究，以确定它们是否在肺部毒性中起致因作用。我们建议 以下两个具体目标：目标1.确定急性和慢性吸入性接触 小鼠体内的维生素E醋酸酯。我们发现，不依赖尼古丁的小鼠肺表面活性物质组成 暴露在慢性接触中会发生改变。一些病人使用的含有大麻的药液 对于急性呼吸衰竭，含有维生素E醋酸酯，这是皮肤科产品中使用的一种常见溶剂。vbl.使用 我们完善的ECG模型，我们将确定急性(两周)或慢性(两个月)维生素T暴露 E醋酸酯单独或与PG/VG联合应用可改变肺表面活性物质。目标2.确定是否 急性或慢性吸入维生素E醋酸酯改变巨噬细胞和/或上皮细胞的功能 在肺里。数百名吸毒者中报告病例的共同临床特征 呼吸衰竭，是以肺部异常为特征的类脂性肺炎的诊断。 含有大量胞浆内脂质的巨噬细胞。鉴于维生素E醋酸酯，已在 ECig产品被一半以上与严重呼吸道疾病相关的病例使用，我们假设它可以 与ECG中的常见溶剂协同作用，以诱导肺免疫和/或上皮细胞的细胞毒性。

Electronic cigarettes (ecigs) gained popularity in never- and active-smokers who are persuaded by intense ad campaigns that brands their use as a healthy alternative to cigarette smoke. Whether heated vaporized contents in ecigs, e.g., propylene glycol (PG), vegetable glycerol (VG) with or without nicotine, are safe alternatives to cigarette smoking remains unknown. We have developed a robust mouse model of conventional and ecig exposure and made several novel discoveries that provide unique insights into the toxicology of ecig in the lungs. In the first year of our funding, we have shown that the popular ecig solvents (e.g., 60/40 ratio of PG/VG), independent of nicotine, can alter lung lipid homeostasis and disrupt the function of alveolar macrophages and epithelial cells (Madison et al, JCI, 2019). We showed that ecig exposure can result in increased abundance of endogenous lipid species normally found in the lung lining fluid, but surfactant proteins (SP)-A, and SP-D associated with these lipids are significantly reduced. Several recent reports have described sporadic cases of ecig (nicotine, and/or cannabis) users who presented with a mysterious (non-infectious) type of lipoid pneumonia. These respiratory illnesses are clinically characterized by dyspnea, fatigue, and in most severe form, respiratory failure and death. Currently the causative factor(s) for the acute respiratory failure in ecig users remains unknown, however the FDA reported that over ½ of the ecig liquid samples linked to the hospitalized patients tested positive for Vitamin E (Vit E) acetate. In this supplemental application, we request funding to examine the acute and chronic effects of Vit E acetate inhalation to determine whether they play a causative role in lung toxicity. We propose the following two Specific Aims: Aim 1. To determine the effect of acute and chronic inhalational exposure to Vitamin E acetate in mice. We have found that independent of nicotine, lung surfactant composition in mice exposed to chronic ecig is altered. The cannabis-containing ecig liquid used by a number of patients who presented with acute respiratory failure, contains Vit E acetate, a common solvent used in dermatological products. Using our well established ecig model, we will determine if acute (two weeks) or chronic (two months) exposure to Vit E acetate alone or in combination with PG/VG can alter surfactant in the lungs. Aim 2. To determine whether acute or chronic inhalation of Vitamin E acetate alters the function of macrophages and/or epithelial cells in the lungs. A common clinical feature of reported cases in several hundred ecig users who have presented with respiratory failure, is the diagnosis of lipoid pneumonia which is characterized by the presence of abnormal lung macrophages that contain large amounts of intracytoplasmic lipids. Given that Vit E acetate, has been found in ecig products used by over half of the cases associated with severe respiratory disease, we hypothesize that it can synergize with the common solvents in ecig to induce cellular toxicity in lung immune and or epithelial cells.