Immunosuppressive injurious effects of e-cigarettes on human lung parenchyma

电子烟对人体肺实质的免疫抑制损伤作用

• 批准号: 10005959
• 负责人: Hong W Chu
• 金额: $ 47.48万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-20 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10005959
• 关键词: Address; Affect; Air; Aldehydes; Anatomy; Antiviral Response; Apoptosis; Autophagocytosis; Biology; Blood Vessels; Cell Adhesion Molecules; Cell Survival; Cellular Structures; Cellular biology; Chronic Obstructive Airway Disease; Clinical; Coculture Techniques; Data; Devices; Distal; Electronic cigarette; Endothelial Cells; Endothelium; Epithelial Cells; Exposure to; Flavoring; Goals; Health; Human; Immune; Immune response; Impairment; Inflammation; Inflammatory; Inflammatory Response; Influenza A virus; Inhalation; Injury; Interferons; Liquid substance; Lung; Lung Inflammation; Mucous Membrane; Natural Immunity; Nicotine; Pathogenesis; Policies; Population; Positioning Attribute; Pulmonary Emphysema; Reactive Oxygen Species; Regulation; Research; Research Proposals; Role; Scientist; Signal Pathway; Signal Transduction; Slice; Sphingolipids; Structure of parenchyma of lung; System; TLR3 gene; Testing; Tissues; Tobacco; Tobacco smoke; Toxicology; Vascular Endothelial Cell; Viral Load result; Viral Respiratory Tract Infection; Virus; Virus Diseases; Work; Youth; airway epithelium; antiviral immunity; cell injury; chemokine; cigarette smoking; cytokine; e-cigarette aerosols; electronic cigarette use; experimental study; exposed human population; exposure to cigarette smoke; improved; lung injury; migration; monolayer; multidisciplinary; neutrophil; respiratory infection virus; response; severe injury; single-cell RNA sequencing; transcriptome sequencing; vapor

Project Summary/Abstract The goal of this two PI research proposal is to determine the immunosuppressive and injurious effects of e- cigarettes on human distal lung structural cells (i.e. small airway epithelial cells and lung microvascular endothelial cells) that are critical to the pathogenesis of chronic obstructive pulmonary disease (COPD), typically induced by tobacco cigarette smoke exposure. The use of e-cigarettes is rapidly increasing in the US youth population, but its health effects on distal lungs have not been investigated. We have found that inhaling e- cigarette vapor (ECVap) can reach small airways to cause distal lung injury. Specifically, we have demonstrated that exposures to ECVap constituents, including nicotine, significantly weaken distal lung (e.g. small airway) innate immunity against influenza A virus infection and microvascular endothelial barrier function, and enhance lung inflammation. We will test the hypothesis that e-cigarettes impair the antiviral immunity, causing increased neutrophilic inflammation and distal lung structural cell (small airway and microvascular endothelial cell) injury by proposing three specific aims. In Aim 1, we will identify the mechanisms whereby ECVap impairs the antiviral immunity of human distal lungs by performing RNA sequencing in precision-cut human (15 to 25 years old) lung slices exposed to ECVap and influenza A viruses (IAV), and carrying out human primary small airway epithelial cell air-liquid interface culture in the presence or absence of ECVap and IAV. In Aim 2, we will determine how ECVap enhances neutrophilic inflammatory response to IAV infection of the human distal lung by using the human lung slices and the co-culture system of human microvascular endothelial cells and neutrophils. In Aim 3, we will determine how ECVap increases distal lung injury following IAV infection by testing if ECVap exposure reduces sphingolipid pro-survival signaling and subsequently increases the vulnerability of small airway epithelial and endothelial cells to virus-induced injury. Research findings from our proposed studies will significantly improve our understanding about the distal lung health effects of e-cigarette use in youth, and inform policies of e-cigarette regulation.

项目总结/摘要 这两项PI研究提案的目标是确定e- 香烟对人远端肺结构细胞（即小气道上皮细胞和肺微血管 内皮细胞），其对慢性阻塞性肺病（COPD）的发病机理至关重要，通常 吸烟引起的。电子烟的使用在美国年轻人中迅速增加 人口，但其对远端肺的健康影响尚未调查。我们发现吸入电子烟- 香烟蒸汽（ECVap）可到达小气道，引起远端肺损伤。具体来说，我们已经证明了 暴露于ECVap成分（包括尼古丁）会显著削弱远端肺（例如小气道） 抗甲型流感病毒感染的天然免疫和微血管内皮屏障功能，并增强 肺部炎症我们将检验电子烟损害抗病毒免疫力的假设， 嗜酸性炎症与远端肺结构细胞（小气道和微血管内皮细胞）损伤 提出三个具体目标。在目标1中，我们将确定ECVap损害抗病毒药物的机制。 通过在精确切割人（15至25岁）肺中进行RNA测序来检测人远端肺的免疫性 暴露于ECVap和甲型流感病毒（IAV）的切片，并进行人原代小气道上皮细胞 在存在或不存在ECVap和IAV的情况下进行细胞气液界面培养。在目标2中，我们将确定如何 ECVap通过使用免疫抑制剂增强人远端肺对IAV感染的嗜肺炎症反应。 人肺切片和人微血管内皮细胞和中性粒细胞的共培养系统。在Aim中 3，我们将确定ECVap如何增加IAV感染后的远端肺损伤， 减少鞘脂促存活信号传导，随后增加小气道上皮细胞的脆弱性， 和内皮细胞对病毒诱导的损伤的影响。我们建议的研究结果将大大 提高我们对年轻人使用电子烟对远端肺部健康影响的理解，并为以下政策提供信息： 电子烟法规