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

提高我们对电子烟或电子烟产品使用相关肺损伤的机制理解

基本信息

批准号：
10115186
负责人：
George Douglas Leikauf
金额：
$ 11.97万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10115186
关键词：
Acetates Acrolein Acute Lung Injury Address Aerosols Affect Alveolar Animal Model Area Atelectasis Attenuated Biological Body Weight decreased Breathing Bronchoalveolar Lavage Cell model Cells Centers for Disease Control and Prevention (U.S.)Cessation of life Chemicals Chest Pain Chlorine Coughing Data Development Devices Diagnosis Diarrhea Diffusion Electronic cigarette Endothelium Epithelial Epithelium Exposure to Fatigue Fever Gases Goals Histology Hour Human Hydralazine Immune Inflammatory Injury Intercellular Fluid Investigation Ion Transport Lead Learning Liquid substance Lung Mediator of activation protein Molecular Mus Nausea and Vomiting Nose Outcomes Research Oxygen Particulate Pathology Patients Perfusion Pharmaceutical Preparations Phenelzine Phenols Phosgene Positioning Attribute Prevention Proteins Public Health Pulmonary Edema Pulmonary Surfactants Recording of previous events Recovery Reporting Respiratory Failure Role Shortness of Breath Stress Symptoms TNF gene Therapeutic Intervention United States Vitamin E Vitamin E Acetate base carbonyl group comparative cytotoxic differential expression electronic cigarette use electronic liquid improved in vivo innovation interest lung injury macrophage marijuana use metabolomics multiple omics pre-clinical prevent proteomic signature response surfactant function toxicant transcriptomics vaping vaping associated lung injury vapor ventilation

项目摘要

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.

抽象的电子烟或烟，产品使用相关肺损伤（evali）已导致2,758例住院患者并导致美国52例死亡（CDC 2019）。大多数评估患者都有E-的病史香烟使用或蒸发以及多数报告使用四氢大麻酚（THC）和维生素E乙酸包含产品。诊断出患有这种疾病的患者报告了咳嗽等症状呼吸或胸痛，恶心，呕吐或腹泻以及疲劳，发烧或体重减轻。多重原因和评估机制仍然不确定，该提案解决了以下关于评估的主要问题在特殊关注通知中概述了：1。我们可以了解涉及的机制评估？ 2。电子液体中的代理（包括热降解产物）如何影响炎症肺上皮，内皮或免疫小球的状态？和3。评估病理或生物学的哪些方面可以在电子烟暴露的细胞或动物模型中概括反应并研究？目的提案是：目标1。部署比较多摩尼克分析以确定转录组的代谢组学小鼠中维生素E乙酸评估的蛋白质组学特征。小鼠将仅鼻子暴露于烟工装置由维生素E醋酸，维生素E，乙酸苯基或苯酚产生的气溶胶。因为维生素E的热解醋酸苯甲酸苯甲酸苯苯乙酸苯酚可以产生酮，这是一种已知毒物的小鼠，也会暴露于酮。肺并将评估支气管肺泡灌洗以进行评估。结果将与我们以前的分析磷酸化，丙烯醛和氯诱导的急性肺损伤。多词分析将用于确定与Lincs L1000CDS 2一起使用的不同表达的签名（DES）以识别预测将扰动评估的药物/分子。这种方法应确定防止的潜在手段或减弱评估。目的2。在评估中获得治疗干预的临床前证据。电子烟蒸气由包括酮和丙烯醛在内的成分和气体的混合物组成，这些混合物会产生羰基胁迫。小鼠将暴露于维生素E醋酸蒸气中，并用针对羰基的剂处理后接触后的暴露后接触组，Hydrolazine和苯嗪。此外，Lincs L10000CDS 2鉴定的两种铅化合物2 将进行评估。评估后，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，并将告知正在进行的调查进入这种疾病及其诊断，治疗和预防。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The role of T cells in the regulation of acrolein-induced pulmonary inflammation and epithelial-cell pathology.

DOI：
发表时间：
2009-12
期刊：
Research report
影响因子：
0
作者：
M. Borchers;S. Wesselkamper;H. Deshmukh;E. Beckman;M. Medvedovic;M. Sartor;G. Leikauf
通讯作者：
M. Borchers;S. Wesselkamper;H. Deshmukh;E. Beckman;M. Medvedovic;M. Sartor;G. Leikauf

When wheeze leads to squeeze: growth under pressure.

当喘息导致挤压时：压力下的增长。