Cellular and molecular mechanisms of e-cigarette vaping-induced acute lung injury

电子烟引起急性肺损伤的细胞和分子机制

• 批准号: 10690279
• 负责人: Yuanpu Peter Di
• 金额: $ 61.64万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-19 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10690279
• 关键词: Acrolein; Acute Lung Injury; Adrenal Cortex Hormones; Aerosols; Alveolar Macrophages; Animal Model; Antioxidants; Apoptotic; Atomizer; CASP3 gene; Cell Death; Cell membrane; Cells; Cessation of life; Chemicals; Cysteine; Data; Development; Diagnosis; Disease Outbreaks; Electronic cigarette; Event; Exposure to; Functional disorder; Future; Generations; HL60; Human; IFN consensus sequence binding protein; Inflammation; Interferons; Investigation; Knowledge; Liquid substance; Mediating; Membrane; Molecular; Molecular Toxicology; Mus; Outcome; Outcomes Research; Pathologic; Pathology; Patients; Phosgene; Phosphatidylserines; Prevention; Public Health; Reactive Oxygen Species; Recovery; Research Personnel; Resolution; Role; Steroid therapy; Steroids; Syndrome; Toxicology; Transcript; United States; Vitamin E Acetate; cellular targeting; cytotoxic; cytotoxicity; electronic liquid; experience; genetic regulatory protein; in vivo; innovation; insight; lung injury; macrophage; novel; perhydroxyl radical; response; single-cell RNA sequencing; toxicant; trend; vaping; vaping associated lung injury; vapor

Abstract The outbreak of electronic-cigarette, or vaping, product use-associated lung injury (EVALI) has led to >2800 hospitalized patients and to >60 deaths in the US. The number of cases peaked between June and September 2019 with a subsequent reduction in trends since then. However, cases continue to occur, emphasizing the need to understand better the underlying mechanism(s) of EVALI. Patient data has led to the hypothesis that vitamin E acetate (VEA) in e-cigarettes can generate a toxic mixture that leads to EVALI. Recently, e-vapor generated from liquid containing VEA has been found to induce lung injury in mice. However, knowledge gaps remain and a need exists to investigate further this hypothesis. This proposal has assembled a team of experienced investigators that are capable of chemical, molecular, and toxicological assessments to provide mechanistic insights into EVALI. We have obtained the following preliminary data: A. VEA e-vapor generated from current sub-ohm vaping devises can produce a novel reactive oxygen species: ethyl peroxyl radical. B. In primary mouse alveolar macrophages, e-vapor extract is cytotoxic and leads to membrane blebbing. C. In RAW 264.7 cells, e- vapor extract increases cell membrane phosphatidylserine externalization. D. In RAW 264.7 cells, e-vapor extract activates caspase 3/7 mediated cell death that can be inhibited by the antioxidant n-acetyl cysteine. E. In mice, single cell RNASeq implicates a number of critical events including decreased macrophage transcripts that are regulated by interferon regulatory protein 8. The hypothesis-driven aims are: 1. Determine the chemical culprits that produce the pathological responses of EVALI. 2. Determine the mechanism of E-vapor induced cell death in alveolar macrophages, and 3. Determine the role of E-vapor-induced decreased interferon regulatory factor 8 in macrophage function. In the latter aim, the mechanisms by which corticosteroid therapy used in EVALI recovery will be investigated. Each aim considers alternative outcomes and strategies. In future studies, our approaches could be applied to flavored e-liquid toxicology. EVALI may have mechanisms that are common to other chemicals (e.g., acrolein or phosgene) known to induce acute lung injury in humans. Thus, the knowledge gained about EVALI pathology and therapy could be applied broadly to chemically-induced acute lung injury. Alternatively, EVALI may be a unique form of acute lung injury and a clearer understanding of its pathology will provide a mechanistic basis for the targeted strategies to treat this syndrome alone.

抽象的 电子烟或烟的爆发与产品使用相关的肺损伤（evali）已导致> 2800 在美国，住院的患者和约60人死亡。案件数量在6月至9月之间达到顶峰 从那以后，2019年随后趋势下降。但是，案件继续发生，强调需求 更好地了解评估的基本机制。患者数据导致了维生素的假设 电子烟中的乙酸盐（VEA）可以产生导致评估的有毒混合物。最近，E-Vapor生成了 已经发现从含有液体的液体中诱导小鼠肺损伤。但是，知识差距仍然存在，并且 存在进一步研究这一假设的需求。该提议组成了一支经验丰富的团队 能够进行化学，分子和毒理学评估以提供机械的研究者 对评估的见解。我们已经获得了以下初步数据：A。 亚欧姆蒸发设计可以产生一种新型的活性氧：乙酰氧基自由基。 B.在主鼠中 肺泡巨噬细胞，电子蒸气提取物是细胞毒性的，导致膜出现。 C.在RAW 264.7细胞中 蒸气提取物增加了细胞膜磷脂酰丝氨酸外在化。 D.在RAW 264.7细胞中，电子蒸气 提取物激活caspase 3/7介导的细胞死亡，该死亡可以被抗氧化剂N-乙酰半胱氨酸抑制。 E. 在小鼠中，单细胞RNASEQ暗示了许多关键事件，包括减少巨噬细胞转录本 由干扰素调节蛋白8调节。假设驱动的目的是：1。确定化学物质 产生评估的病理反应的罪魁祸首。 2。确定电子蒸气诱导的细胞的机制 肺泡巨噬细胞的死亡和3。确定电子蒸气诱导的干扰素调节的作用 巨噬细胞功能中的因子8。在后一个目的中，皮质类固醇治疗用于评估的机制 恢复将进行调查。每个目标都考虑替代结果和策略。在未来的研究中，我们的 方法可以应用于调味的电子液体毒理学。评估可能具有常见的机制 已知的其他化学物质（例如丙烯醛或磷酸化学物质）诱导人类急性肺损伤。因此，知识 在评估病理学和治疗方面获得的获得可广泛应用于化学诱导的急性肺损伤。 另外，评估可能是急性肺损伤的一种独特形式，对其病理的清晰了解将会 为单独治疗该综合征的目标策略提供机械基础。