Effect of Traffic-Related Pollutants on Airway Beta2-Adrenergic Receptors

交通相关污染物对气道 β2 肾上腺素能受体的影响

基本信息

批准号：
8279276
负责人：
Phillip H Factor
金额：
$ 32.1万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-06-01 至 2013-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8279276
关键词：
Address Adenylate Cyclase Adipocytes Adrenergic Agonists Adrenergic Receptor Affect Age Air Pollutants Air Pollution Aromatic Polycyclic Hydrocarbons Asthma Attenuated Binding Breathing Bronchoconstriction Catecholamines Cell Line Cells Child Childhood Asthma Complement Controlled Study Cyclic AMP Data Diesel Exhaust Disease Engine Exhaust Environment Environmental Health Epithelial Epithelial Cells Exposure to Extrinsic asthma Finding by Cause Forskolin Gene Transfer Genetically Engineered Mouse Goals Health Hour Human Immunization In Vitro Interruption Link Lung Measures Mediating Membrane Methods Modeling Molecular Motor Vehicles Mus New York City Newborn Infant Ovalbumin Pathogenesis Perinatal Exposure Pharmaceutical Preparations Predisposition Pregnancy Procaterol Production Receptor Signaling Relaxation Role Signal Transduction Pathway Smooth Muscle Myocytes Testing Time Study Work aerosolized attenuation clinically relevant cohort constriction early life exposure in utero in vivo insight model design mouse model novel pollutant pregnant programs receptor binding receptor expression receptor function research study respiratory smooth muscle tool trafficking

项目摘要

Traffic related air pollution includes diesel engine exhaust derived polycyclic aromatic hydrocarbons (PAH) that have been linked with asthma. Inhaled B{2}-adrenergic agonists engage membrane bound B{2}-adrenergic receptors (B{2}AR) on airway epithelial and smooth muscle cells to cause airway dilation. Preliminary data produced for this application indicate that a diesel exhaust derived mixture of PAHs (DDPAH) impede B{2}AR mediated airway dilation in normal mice and mice with ovalbumin-induced allergic asthma. In vitro studies indicate that DDPAH attenuates B{2}AR function in airway epithelial and smooth muscle cells. These new findings caused us to hypothesize that traffic-related PAH may impede B{2}AR mediated airway relaxation in asthmatics. This hypothesis suggests a new paradigm where air pollutants not only worsen childhood asthma but diminish responsiveness to standard therapy. To test this hypothesis we are proposing 3 aims regarding the effect of traffic-related PAH (TR-PAH) on airway B{2}AR function. Aim 1: Determine if traffic-related PAHs affect B{2}AR expression and function in airway epithelial cells in vitro. Primary mouse tracheal epithelial (MTE) and human airway epithelial cells will be treated with environmentally relevant concentrations of a DDPAH or a mixture of PAH that matches exposures of children in the CCCEH cohort described in project 1 (CCCEH-PAH) prior to assessment of the B{2}AR and its signal transduction pathway. Aim 2: Ascertain if traffic-related PAHs affect B{2}AR function in airway smooth muscle cells in vitro. Human airway smooth muscles cells will be exposed to environmentally relevant concentrations of DDPAH or CCCEH-PAH prior to assessment of the B{2}AR and its signal transduction pathway. Aim 3: Determine if TR-PAHs alter airway B{2}AR function following in utero and early life exposures? The experiments in this aim will test if prolonged exposure to DDPAH or CCCEH-PAH alters B{2}AR -mediated reductions in airways reactivity in young mice. These experiments will utilize mouse models of in utero and early-life exposure that model the windows of asthma susceptibility being investigated in projects 1, 2, and 3. These experiments will be conducted in normal mice, mice with allergic asthma (ovalbumin immunization and rechallenge), mice with targeted deletions of the B{2}AR, and mice with interruption of epithelial cell B{2}AR function. The focused studies within these aims incorporate environmentally relevant PAH exposures, molecular tools, clinically relevant cell lines, genetically engineered mice, and gene transfer to generate models that will allow us address a novel hypothesis regarding the interaction of airborne pollutants and asthma. These experiments complement the studies outlined throughout this DISCOVER project to provide new insights into how common air pollutants affect children's lung health.

与交通相关的空气污染包括柴油发动机废气产生的多环芳烃（PAH），它与哮喘有关。吸入的 B{2}-肾上腺素能激动剂与气道上皮细胞和平滑肌细胞上的膜结合 B{2}-肾上腺素能受体 (B{2}AR) 结合，引起气道扩张。该应用产生的初步数据表明，柴油机尾气衍生的 PAH 混合物 (DDPAH) 会阻碍正常小鼠和患有卵清蛋白诱导过敏性哮喘的小鼠中 B{2}AR 介导的气道扩张。体外研究表明，DDPAH 会减弱气道上皮细胞和平滑肌细胞中的 B{2}AR 功能。这些新发现使我们推测交通相关的 PAH 可能会阻碍哮喘患者 B{2}AR 介导的气道松弛。这一假设提出了一种新的范式，其中空气污染物不仅会使儿童哮喘恶化，还会降低对标准治疗的反应。为了检验这一假设，我们针对交通相关 PAH (TR-PAH) 对气道 B{2}AR 功能的影响提出了 3 个目标。目标 1：确定与交通相关的 PAH 是否影响体外气道上皮细胞中的 B{2}AR 表达和功能。原代小鼠气管上皮 (MTE) 和人气道上皮细胞将用环境相关浓度的 DDPAH 或 PAH 混合物进行处理，该浓度与项目 1 (CCCEH-PAH) 中描述的 CCCEH 队列中儿童的暴露量相匹配，然后再评估B{2}AR及其信号转导通路。目标 2：确定与交通相关的 PAH 是否会影响体外气道平滑肌细胞的 B{2}AR 功能。在评估 B{2}AR 及其信号转导途径之前，人类气道平滑肌细胞将暴露于环境相关浓度的 DDPAH 或 CCCEH-PAH。目标 3：确定 TR-PAH 是否会改变子宫内和早期生命暴露后的气道 B{2}AR 功能？此目的的实验将测试长期暴露于 DDPAH 或 CCCEH-PAH 是否会改变 B{2}AR 介导的幼鼠气道反应性降低。这些实验将利用子宫内和生命早期暴露的小鼠模型来模拟项目 1、2 和 3 中正在研究的哮喘易感性窗口。这些实验将在正常小鼠、患有过敏性哮喘的小鼠中进行（卵清蛋白免疫和再激发））、B{2}AR 定向删除的小鼠以及上皮细胞 B{2}AR 功能中断的小鼠。这些目标的重点研究包括环境相关的多环芳烃暴露、分子工具、临床相关细胞系、基因工程小鼠和基因转移，以生成模型，使我们能够提出关于空气污染物与哮喘相互作用的新假设。这些实验补充了整个 DISCOVER 项目中概述的研究，以提供有关常见空气污染物如何影响儿童肺部健康的新见解。