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与哮喘相关的柴油机排气衍生的多环芳烃（PAH）。吸入B {2} - 肾上腺素能激动剂在气道上皮和平滑肌细胞上与膜结合B {2} - 肾上腺素能受体（B {2} AR）引起气道扩张。针对此应用产生的初步数据表明，PAHS（DDPAH）的柴油排气衍生的混合物阻碍了正常小鼠中的B {2} AR介导的气道扩张，而小鼠则具有卵蛋白诱导的过敏性哮喘。体外研究表明，DDPAH会减弱B {2} AR在气道上皮和平滑肌细胞中的功能。这些新发现使我们假设与交通相关的PAH可能会阻碍B {2} AR介导的气道在哮喘患者中放松。该假设表明了一种新的范式，其中空气污染物不仅使童年哮喘恶化，而且会降低对标准治疗的反应性。为了检验这一假设，我们提出了3个目标，涉及与交通相关的PAH（TR-PAH）对气道B {2} AR函数的影响。 AIM 1：确定与交通相关的PAHs是否影响B {2} AR表达和在体外气道上皮细胞中的功能。原发性小鼠气管上皮（MTE）和人气道上皮细胞将用与环境相关的DDPAH浓度或PAH混合物进行处理，与Project 1（CCCEH-PAH）中描述的CCCEH队列中的儿童暴露相匹配，然后评估B {2} AR及其信号传递路径。 AIM 2：确定与交通相关的PAH是否影响B {2} AR在体外气道平滑肌细胞中的功能。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的DDPAH或CCCEH-PAH。 AIM 3：确定TR-PAH是否在子宫和早期生活中发生airway B {2} AR功能？此目标中的实验将测试是否长时间暴露于DDPAH或CCCEH -PAH会改变年轻小鼠气道反应性的降低B {2} AR介导的降低。这些实验将利用子宫内和早期暴露的鼠标模型，该模型模拟了项目1、2和3中研究的哮喘易感性窗口。这些实验将在正常小鼠中进行，具有过敏性哮喘（Ovalbumin Ambinization and rechallenge），具有靶标的小鼠的小鼠，具有b cylial的小鼠，并具有b ricial b.2} art和2} art和2} art and cyrial cell和2} art和2} art和cyl cart的2个} rycial和2} art和2} art和cyl。 b {2} ar函数。这些目的中的重点研究结合了与环境相关的PAH暴露，分子工具，临床相关的细胞系，基因工程小鼠以及基因转移，以生成模型，这将使我们解决有关空气中污染物和哮喘相互作用的新假设。这些实验补充了整个发现项目中概述的研究，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。