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

• 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
• 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

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尾气中产生的与哮喘有关的多环芳烃(PAH)。吸入的B{2}-肾上腺素能激动剂与呼吸道上皮细胞和平滑肌细胞膜上的B{2}-肾上腺素能受体(B{2}-AR)结合，引起呼吸道扩张。初步数据表明，柴油尾气衍生的多环芳烃混合物(DDPAH)可抑制正常小鼠和卵蛋白诱导的过敏性哮喘小鼠的B{2}AR介导的气道扩张。体外研究表明，DDPAH可减弱呼吸道上皮细胞和平滑肌细胞的B{2}AR功能。这些新的发现使我们推测，交通相关的PAH可能会阻碍B{2}AR介导的哮喘患者的气道松弛。这一假设提出了一种新的范式，即空气污染物不仅会加重儿童哮喘，还会降低对标准治疗的反应性。为了验证这一假设，我们提出了关于交通相关PAH(TR-PAH)对气道B{2}AR功能的影响的3个目标。 目的1：研究交通相关多环芳烃是否会影响体外培养的呼吸道上皮细胞B{2}AR的表达和功能。原代小鼠气管上皮(MTE)和人类呼吸道上皮细胞将在评估B{2}AR及其信号转导途径之前，用与项目1(CCCEH-PAH)中描述的CCCEH队列中儿童暴露相匹配的环境相关浓度的DDPAH或PAH的混合物处理。 目的2：探讨交通相关多环芳烃对体外培养的气道平滑肌细胞B2受体功能的影响。在评估B{2}AR及其信号转导途径之前，人的呼吸道平滑肌细胞将暴露于与环境相关的浓度的DDPAH或CCCEH-PAH。 目的3：确定在宫内和生命早期暴露后，tr-PAHs是否会改变呼吸道B{2}AR功能？这个目的的实验将测试长期暴露于DDPAH或CCCEH-PAH是否改变B{2}AR介导的幼鼠呼吸道反应性的降低。这些实验将利用在宫内和早期暴露的小鼠模型，模拟项目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、过敏性哮喘小鼠(卵蛋白免疫和再激发)、定向缺失B{2}AR的小鼠和上皮细胞B{2}AR功能中断的小鼠中进行。 这些目标中的重点研究包括与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，以产生模型，使我们能够解决关于空气污染物和哮喘相互作用的新假说。这些实验补充了整个发现项目中概述的研究，以提供关于常见空气污染物如何影响儿童肺部健康的新见解。