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.

项目摘要/摘要电子烟中的许多调味化学物质都呈现出一类电子烟的化学物质，可能是引起明显的不良健康影响。几种电子液体调味化合物是α，β-不饱和醛，A 对呼吸免疫功能有已知不良影响的化学物质类别。在这些调味料中化合物是肉桂醛（CA），一种经常包含在流行肉桂或辛辣的电子液体和已知的免疫调节活动。但是，CA的潜在影响呼吸免疫反应具有关键的知识差距，这将是本应用的重点。我们将使用体外研究中紧密相连的机械和人类研究来确定CA的不利影响呼吸有先天免疫功能，具体关注两个组成部分：1）粘膜成分由衬里的纤毛上皮细胞组成，2）由居民和浸润白细胞，例如巨噬细胞（MAC）。我们的数据表明，含有CA的电子液体大大以不会引起明显细胞毒性的剂量影响睫状跳动和呼吸免疫细胞功能。这些影响与修饰的线粒体呼吸有关，可以通过还原硫醇抑制试剂。根据现有知识和我们自己的数据，我们假设含有CA的电子液体通过CA诱导的线粒体呼吸和硫醇抑制先天粘膜免疫功能细胞蛋白的修饰。我们将以两个具体的目的检验这一假设：SA1将确定CA- 诱导对上皮睫状功能和粘膜纤毛清除（MCC）的影响，并确定机制调解这些反应。为了实现这一目标，我们将揭示差异化的人支气管上皮细胞（HBEC）到含CA的电子液体，评估睫毛的变化，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受控吸入Technetium-99m硫吸入CA的电子烟后，胶体（TC99M-SC）颗粒，然后跟踪使用伽玛闪烁显像的放射性标记颗粒作为MCC的量度。 SA2将确定CA诱导的 MAC的调节和介导这些反应的机制。为了实现这一目标，我们将刺激具有含CA的电子液体的人类Mac在体内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。通过诱导获得的Mac 来自人类受试者的痰液（IS）受到受控vap vap to含CA的电子液体的持续暴露是用于将MAC在体内获得的机械发现转化为体内人类。来自这些高度综合的翻译研究将产生有关流行电子的重要机械信息香烟调味剂对较大的化学调味剂具有潜在影响，因此解决与使用电子烟的潜在健康影响有关的临床知识差距。