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

基本信息

批准号：
10241973
负责人：
Hong W Chu
金额：
$ 46.59万
依托单位：
NATIONAL JEWISH HEALTH
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-20 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10241973
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

项目摘要

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.

项目概要/摘要这两项 PI 研究计划的目标是确定电子的免疫抑制和伤害作用香烟对人远端肺结构细胞（即小气道上皮细胞和肺微血管）的影响内皮细胞）对慢性阻塞性肺疾病（COPD）的发病机制至关重要，通常由接触烟草烟雾引起。美国青少年电子烟的使用量迅速增加人群，但尚未研究其对远端肺部健康的影响。我们发现吸入电子香烟蒸气 (ECVap) 可到达小气道，导致远端肺损伤。具体来说，我们已经证明了接触 ECVap 成分（包括尼古丁）会显着削弱远端肺（例如小气道）对抗甲型流感病毒感染的先天免疫和微血管内皮屏障功能，并增强肺部炎症。我们将检验以下假设：电子烟会损害抗病毒免疫力，导致增加中性粒细胞炎症和远端肺结构细胞（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对精确切割的人（15 至 25 岁）肺进行 RNA 测序来提高人远端肺的免疫力暴露于 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 通过使用以下物质增强人类远端肺 IAV 感染的中性粒细胞炎症反应人肺切片以及人微血管内皮细胞和中性粒细胞的共培养系统。瞄准 3，我们将通过测试 ECVap 暴露情况来确定 ECVap 如何增加 IAV 感染后的远端肺损伤减少鞘脂促生存信号传导，随后增加小气道上皮的脆弱性和内皮细胞对病毒引起的损伤。我们提出的研究结果将显着提高我们对青少年使用电子烟对远端肺部健康影响的了解，并为相关政策提供信息电子烟监管。