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 电子烟或电子烟产品使用相关肺损伤 (EVALI) 的爆发已导致超过 2800 在美国，有超过 60 名患者住院并死亡。病例数量在六月至九月期间达到顶峰 2019 年，此后趋势有所减少。然而，案件不断发生，强调需要 更好地了解 EVALI 的基本机制。患者数据得出这样的假设：维生素 电子烟中的醋酸酯 (VEA) 会产生有毒混合物，导致 EVALI。最近，电子蒸气产生 已发现含有 VEA 的液体会引起小鼠肺损伤。然而，知识差距依然存在 需要进一步研究这一假设。该提案组建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制的研究人员 对 EVALI 的见解。我们获得了以下初步数据： A. 由电流产生的 VEA 电子蒸气 亚欧姆电子烟装置可以产生一种新型活性氧：乙基过氧自由基。 B. 在原代小鼠中 肺泡巨噬细胞中，电子蒸气提取物具有细胞毒性并导致膜起泡。 C. 在 RAW 264.7 细胞中，e- 蒸气提取物增加细胞膜磷脂酰丝氨酸的外化。 D. 在 RAW 264.7 细胞中，电子蒸汽 提取物激活 caspase 3/7 介导的细胞死亡，该细胞死亡可被抗氧化剂 n​​-乙酰半胱氨酸抑制。 E. 在小鼠中，单细胞 RNASeq 涉及许多关键事件，包括巨噬细胞转录物减少 受干扰素调节蛋白 8 调节。假设驱动的目标是： 1. 确定化学物质 产生 EVALI 病理反应的罪魁祸首。 2. 确定电子蒸汽诱导细胞的机制 肺泡巨噬细胞死亡，以及 3. 确定电子蒸汽诱导的干扰素调节下降的作用 巨噬细胞功能中的因子 8。在后一个目标中，皮质类固醇治疗用于 EVALI 的机制 恢复情况将受到调查。每个目标都考虑替代结果和策略。在今后的研究中，我们 这些方法可应用于调味电子烟液毒理学。 EVALI 可能具有以下共同机制： 已知可引起人类急性肺损伤的其他化学物质（例如丙烯醛或光气）。由此可见，知识 关于 EVALI 病理学和治疗的知识可广泛应用于化学诱导的急性肺损伤。 另外，EVALI 可能是急性肺损伤的一种独特形式，对其病理学的更清晰了解将有助于 为单独治疗该综合征的靶向策略提供机制基础。