E-cig flavors and their effects on respiratory innate immune responses

电子烟口味及其对呼吸道先天免疫反应的影响

基本信息

批准号：
10011941
负责人：
ILONA JASPERS
金额：
$ 49.57万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-15 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10011941
关键词：
Address Adolescent Adult Adverse effects Aerosols Affect Aldehydes Cell physiology Cells Chemicals Cigarette Cigarette Smoker Ciliary epithelium Cinnamon - dietary Clinical Colloids Core-Binding Factor Cysteine Data Dose Electronic cigarette Epithelial Epithelial Cells Epithelium Exposure to Flavoring Food Frequencies Functional disorder Gene Expression Health Human Human Volunteers Immune Immune response Immunosuppression In Vitro Inhalation Innate Immune Response Knowledge Leukocytes Link Measures Mediating Mediator of activation protein Mitochondria Modeling Modification Mucociliary Clearance Mucosal Immune Responses Mucous Membrane Nicotine Dependence Phenotype Predisposition Production Proteins Radiolabeled Radionuclide Imaging Reagent Reporting Respiration Respiratory Mucosa Respiratory Tract Infections Role Signaling Molecule Smoker Smoking Sputum Structure of mucous membrane of nose Sulfhydryl Compounds Sulfur Surface Surgeon System Technetium 99m Teenagers Testing Tobacco Toxic effect Translating Translational Research airway epithelium antimicrobial arm base bronchial epithelium chemical group cigarette smoking cinnamic aldehyde clinically relevant cytotoxic cytotoxicity e-cigarette aerosols electronic cigarette use electronic cigarette user electronic liquid experimental study human subject immune function in vitro Model in vivo innate immune function innovation macrophage non-smoker novel particle respiratory response translational study vaping volunteer young adult

项目摘要

Project Summary/Abstract Many of the flavoring chemicals in e-cigarettes present a class of chemicals unique to e-cigarettes, potentially causing distinct adverse health effects. Several e-liquid flavoring compounds are α,β-unsaturated aldehydes, a class of chemicals with known adverse effects on respiratory immune function. Among those flavoring compounds is cinnamaldehyde (CA), an α,β-unsaturated aldehyde often contained in popular cinnamon or spicy flavored e-liquids and with known immune modulating activities. However, potential effects of CA on respiratory immune responses present a critical knowledge gap, which will be the focus of this application. We will use tightly linked mechanistic in vitro and human in vivo studies to determine adverse effects of CA on respiratory innate immune functions, with specific focus on two components: 1) the mucociliary component consisting of ciliated epithelial cells lining the airways and 2) the cellular component consisting of resident and infiltrating leukocytes, such as macrophages (Macs). Our data demonstrate that CA-containing e-liquids greatly affect ciliary beating and respiratory immune cell function at doses that do not cause overt cytotoxicity. These effects were associated with modified mitochondrial respiration and could be inhibited by thiol reducing reagents. Thus, based on existing knowledge and our own data we hypothesize that CA-containing e-liquids suppress innate mucosal immune function by CA-induced inhibition of mitochondrial respiration and thiol modification of cellular proteins. We will test this hypothesis in two specific aims: SA1 will determine CA- induced effects on epithelial ciliary function and mucociliary clearance (MCC) and identify the mechanisms mediating these responses. To achieve this aim we will expose well-differentiated human bronchial epithelial cells (HBECs) to CA-containing e-liquids, assess changes in ciliary beating, and determine the role of mitochondrial respiration and thiol modification in these responses. To translate these findings into humans in vivo, we propose to have healthy adult volunteers undergo controlled inhalation of Technetium-99m sulfur colloid (Tc99m-SC) particles after inhalation of CA-containing e-cigarettes, followed by tracking the egress of the radiolabeled particles as a measure of MCC using gamma scintigraphy. SA2 will determine CA-induced modulation of Macs and the mechanisms mediating these responses. To achieve this aim we will stimulate human Macs with CA-containing e-liquids ex vivo and examine changes in immune function, and determine the role of thiol modification and mitochondrial respiration in these responses. Macs obtained through induced sputum (IS) from human subjects undergoing controlled vaping exposure to CA-containing e-liquids will be used to translate the mechanistic findings obtained in Macs ex vivo into humans in vivo. Data derived from these highly integrated translational studies will yield important mechanistic information on a popular e- cigarette flavoring agent with potential implications for a larger group of chemical flavoring agents, thus addressing a clinical knowledge gap related to the potential health effects of flavored e-cigarette use.

项目概要/摘要电子烟中的许多调味化学品呈现出电子烟特有的一类化学物质，可能几种电子烟液调味化合物是 α,β-不饱和醛、已知对呼吸道免疫功能有不利影响的一类化学物质。化合物是肉桂醛（CA），一种α,β-不饱和醛，通常包含在流行的肉桂或辛辣味电子烟油并具有已知的免疫调节活性，但 CA 对免疫的潜在影响。呼吸道免疫反应存在一个关键的知识缺口，这将是本应用的重点。将使用紧密相连的体外和人体体内研究机制来确定 CA 对呼吸道先天免疫功能，特别关注两个组成部分：1）粘膜纤毛成分由气道内衬的纤毛上皮细胞组成，2) 细胞成分由常驻和浸润性白细胞，例如巨噬细胞 (Mac) 我们的数据表明，含有 CA 的电子烟液具有显着的作用。在不引起明显细胞毒性的剂量下影响纤毛跳动和呼吸道免疫细胞功能。影响与改变线粒体呼吸有关，并且可以通过硫醇还原来抑制因此，根据现有知识和我们自己的数据，我们捕获了含有 CA 的电子液体。通过 CA 诱导的线粒体呼吸和硫醇抑制来抑制先天粘膜免疫功能我们将在两个特定目标中检验这一假设： SA1 将决定 CA- 对上皮纤毛功能和粘液纤毛清除（MCC）的诱导影响并确定其机制为了实现这一目标，我们将暴露分化良好的人类支气管上皮。细胞 (HBEC) 与含有 CA 的电子液体，评估纤毛跳动的变化，并确定这些反应中的线粒体呼吸和硫醇修饰将这些发现转化为人类。 vivo，我们建议让健康的成年志愿者进行受控吸入Technetium-99m硫吸入含CA电子烟后的胶体（Tc99m-SC）颗粒，随后追踪其排出情况使用伽马闪烁扫描法测量 MCC 的放射性标记颗粒将确定 CA 诱导的。为了实现这一目标，我们将刺激 Mac 的调节和调节这些反应的机制。人类 Mac 与含有 CA 的电子液体离体并检查免疫功能的变化，并确定硫醇修饰和线粒体呼吸在这些反应中的作用。接受受控电子烟暴露于含 CA 电子液体的人类受试者的痰 (IS) 将被用于将 Mac 离体获得的机械发现转化为人类体内数据。这些高度综合的转化研究将产生关于流行的电子学的重要机制信息。卷烟调味剂对一大类化学调味剂具有潜在影响，因此解决与使用调味电子烟的潜在健康影响相关的临床知识差距。