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

电子香烟（ecigs）在从不吸烟和经常吸烟的人中越来越受欢迎，他们被强烈的广告所说服。 宣传活动将其作为香烟烟雾的健康替代品。加热蒸发的内容物是否在 电子烟，例如，丙二醇（PG），植物甘油（VG），含或不含尼古丁，是安全的替代品， 吸烟仍然是未知的。我们已经开发了一个强大的小鼠模型的常规和ecig暴露 并取得了一些新的发现，为肺中ecig的毒理学提供了独特的见解。在 在我们资助的第一年，我们已经表明流行的CIG溶剂（例如，PG/VG的60/40比率），独立 尼古丁，可以改变肺脂质稳态，破坏肺泡巨噬细胞和上皮细胞的功能 （麦迪逊等人，JCI，2019）。我们发现暴露于ecig可导致内源性脂质丰度增加 通常在肺衬里液中发现的物质，但表面活性蛋白（SP）-A和SP-D与这些物质相关 脂质显著减少。最近的几份报告描述了ecig（尼古丁和/或 大麻）用户谁提出了一个神秘的（非传染性）类型的类脂肺炎。这些呼吸 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，引起ecig使用者急性呼吸衰竭的原因尚不清楚， FDA报告说，与住院患者有关的ecig液体样本中有一半以上的维生素检测呈阳性。 E（维生素E）乙酸酯。在这份补充申请中，我们要求资助研究急性和慢性影响， 醋酸维生素E吸入，以确定它们是否在肺毒性中发挥致病作用。我们建议 有两个具体目标：目标1。确定急性和慢性吸入暴露对 维生素E醋酸酯。我们已经发现，独立于尼古丁，小鼠肺表面活性物质的组成 暴露于慢性EIG的人改变了。一些病人使用的含有大麻的ecig液体， 含有维生素E醋酸酯，一种用于皮肤科产品的常见溶剂。使用 我们建立了良好的ecig模型，我们将确定是否急性（两周）或慢性（两个月）暴露于维生素 E醋酸盐单独或与PG/VG组合可改变肺中的表面活性剂。目标2.以确定是否 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 在肺部。在数百名出现以下症状的ecig使用者中报告的病例的一个共同临床特征是 呼吸衰竭是类脂性肺炎的诊断，其特征在于存在异常肺 含有大量胞浆内脂质的巨噬细胞。鉴于维生素E醋酸酯，已被发现在 超过一半的严重呼吸道疾病病例使用了ecig产品，我们假设它可以 与CIG中的常用溶剂协同作用，以诱导肺免疫细胞和/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.