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

摘要 电子烟或电子烟产品使用相关肺损伤(EVALI)已导致2758名住院患者 并已导致美国52人死亡(CDC 2019)。大多数EVALI患者都有e- 香烟的使用或蒸发，大多数报告使用四氢大麻酚(THC)和维生素E醋酸酯 包含产品。被诊断为这种疾病的患者报告了诸如咳嗽、短促等症状。 呼吸或胸痛、恶心、呕吐或腹泻，以及疲劳、发烧或体重减轻。多重原因和 EVALI的机制仍不确定本提案解决了以下有关EVALI的主要问题 在《特别关注通知》中概述：1.我们可以从参与发展的机制中了解到什么 EVALI？2.电子液体中的试剂，包括热降解产品，如何影响炎症 肺上皮细胞、内皮细胞还是免疫细胞的状态？3.EVALI病理学或生物学的哪些方面 可以在暴露于电子烟的细胞或动物模型中概括和研究反应吗？该计划的目标是 建议：目标1.采用比较多组学分析来确定转录、代谢组学 以及维生素E醋酸酯EVALI在小鼠中的蛋白质组学特征。老鼠将只有鼻子接触蒸发设备 由维生素E醋酸酯、维生素E、乙酸苯酯或苯酚产生的气雾剂。因为维生素E的热解 乙酸乙酯或乙酸苯酯会产生乙烯酮，这是一种已知的有毒物质，老鼠也会接触到乙烯酮。肺 并将评估支气管肺泡灌洗以寻找EVALI的证据。结果将与我们之前的结果进行比较 光气、丙烯醛和氯气致急性肺损伤的分析。多元经济分析将被用于 识别与LINCS L1000CDS 2一起使用的差异表达签名(DES)以识别 预计会扰乱EVALI的试剂/分子。这一方法应该确定潜在的预防手段 或减弱EVALI。目的2.为EVALI的治疗干预提供临床前证据。电子烟蒸气 由微粒和包括乙烯酮和丙烯醛在内的气体的混合物组成，这些气体会产生羰基压力。 小鼠将暴露在维生素E醋酸酯蒸气中，并在暴露后使用针对羰基的试剂进行治疗 联苯肼和苯乙肼。此外，Lincs L10000CDS 2鉴定的两种先导化合物 将会被评估。EVALI后，将评估小鼠肺内的支气管肺泡灌洗、组织学和DES。 这项研究的结果将对公众健康产生重大影响，并将为正在进行的调查提供信息 探讨这种疾病及其诊断、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.