Improving our mechanistic understanding of Electronic-cigarette, or vaping, product use-associated lung injury

摘要 电子烟或vaping产品使用相关的肺损伤（EVALI）已导致2，758名住院患者 并导致美国52人死亡（CDC 2019）。大多数EVALI患者有e- 吸烟或吸电子烟，大多数人报告使用四氢大麻酚（THC）和维生素E醋酸酯 包含产品。被诊断患有这种疾病的患者报告了咳嗽，气短， 呼吸或胸痛、恶心、呕吐或腹泻、疲劳、发烧或体重减轻。多种原因和 该提案解决了以下关于EVALI的主要问题， 特别关注的通知概述：1。我们能从发展中的机制中了解到什么 关于EVALI？2.电子液体中的试剂，包括热降解产物，如何影响炎症反应？ 肺上皮细胞、内皮细胞或免疫细胞的状态？和3. EVALI病理学或生物学的哪些方面 反应可以概括和研究的细胞或动物模型的电子烟暴露？的目标 建议是：目标1。部署比较多组学分析，以确定转录组学、代谢组学 和蛋白质组签名的维生素E醋酸酯EVALI在小鼠中。小鼠将只暴露于鼻子上的电子烟装置 由维生素E乙酸酯、维生素E、乙酸苯酯或苯酚产生的气溶胶。因为维生素E的热解 乙酸或乙酸苯酯可产生乙烯酮，一种已知的毒物，小鼠也将暴露于乙烯酮。肺 并将评估支气管肺泡灌洗的EVALI证据。结果将与我们之前的 光气、丙烯醛和氯诱导的急性肺损伤的分析。多组学分析将用于 识别与LINCS L1000CDS 2一起使用的差异表达签名（DES），以识别 预计会干扰EVALI的试剂/分子。这一方法应确定潜在的预防手段， 或减弱EVALI。目标2.获得EVALI治疗干预的临床前证据。电子烟蒸汽 由颗粒和气体的混合物组成，包括乙烯酮和丙烯醛，其可以产生羰基应激。 将小鼠暴露于维生素E醋酸酯蒸汽，并在暴露后用针对羰基的试剂进行治疗 组：肼苯哒嗪和苯乙肼。此外，LINCS L10000CDS 2鉴定的两种先导化合物 将被评估。在EVALI后，将在小鼠肺中评估支气管肺泡灌洗、组织学和DES。 这项研究的结果将对公共卫生产生重大影响，并将为正在进行的调查提供信息。 以及它的诊断、治疗和预防。

Abstract Electronic-cigarette, or vaping, product use–associated lung injury (EVALI) has led to 2,758 hospitalized patients and has led to 52 deaths in the United States (CDC 2019). Most of the EVALI patients have a history of e- cigarette use or vaping and the majority report using tetrahydrocannabinol (THC) and vitamin E acetate containing products. Patients diagnosed with this illness have reported symptoms such as cough, shortness of breath or chest pain, nausea, vomiting or diarrhea, and fatigue, fever, or weight loss. The multiple causes and mechanisms of EVALI remain uncertain This proposal addresses the following major concerns about EVALI as outlined in the Notice of Special Interest: 1. What can we learn about mechanisms involved in the development of EVALI? 2. How do the agents in e-liquids, including thermal degradation products, affect the inflammatory state of pulmonary epithelia, endothelia, or immune cells? and 3. What aspects of EVALI pathology or biological response can be recapitulated and studied in cell or animal models of e-cigarette exposure? The aims of the proposal are: Aim 1. Deploy a comparative multi-omic analysis to determine the transcriptomic, metabolomic and proteomic signature of vitamin E acetate EVALI in mice. Mice will be exposed nose-only to a vaping device aerosols generated from vitamin E acetate, vitamin E, phenyl acetate, or phenol. Because pyrolysis of vitamin E acetate or phenyl acetate can generate ketene, a known toxicant, mice will also be exposed to ketene. Lungs and bronchoalveolar lavage will be assessed for evidence of EVALI. The results will be compared to our previous analysis of phosgene-, acrolein-, and chlorine-induced acute lung injury. Multi-omic analysis will be used to identify a differentially expressed signature (DES) for use with the LINCS L1000CDS 2 to identify agents/molecules that are predicted to perturb EVALI. This approach should identify potential means to prevent or attenuate EVALI. Aim 2. Obtain preclinical evidence for therapeutic intervention in EVALI. E-cigarette vapors consist of a mixture of particulates and gases including ketene and acrolein, which can generate carbonyl stress. Mice will be exposed to vitamin E acetate vapor and treated post-exposure with agents directed at carbonyl groups, hydralazine and phenelzine. In addition, two of the lead compounds identified by LINCS L10000CDS 2 will be evaluated. Bronchoalveolar lavage, histology, and DES will be assessed in mouse lung following EVALI. The outcome of this research will have substantial public health impact and will inform the ongoing investigation into this illness as well as its diagnosis, treatment, and prevention.