Role of macrophages in organophosphorus pesticide-induced airway hyperreactivity

巨噬细胞在有机磷农药引起的气道高反应性中的作用

基本信息

批准号：
8106431
负责人：
ALLISON Deborah FRYER
金额：
$ 34.24万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-07 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8106431
关键词：
Acetylcholine Acetylcholinesterase Address Agonist Allergic Alveolar Macrophages Animals Antigens Asthma Brain Bronchoalveolar Lavage Bronchoconstriction Carbamates Cavia Cell Culture Techniques Child Cholinesterases Coculture Techniques Data Dichloromethylene Diphosphonate Dose Encapsulated Epidemiologic Studies Exposure to Functional disorder Funding Goals Grant Health Human Individual Inflammation Inflammatory Insecticides Interferons Interleukin-5 Light Link Liposomes Lung Measurement Measures Mediating Mediator of activation protein Messenger RNA Modeling Molecular Morphology Muscarinic M2 Receptor Nerve Neuronal Plasticity Neurons Ozone Parathion Pesticides Physiological Pilocarpine Prevalence Preventive Proteins Public Health Rattus Reporting Risk Role Saline Site Structure Structure of parenchyma of lung Symptoms TNF gene Testing Therapeutic Time United States National Institutes of Health Work airway hyperresponsiveness cytokine eosinophil exposed human population functional loss in vivo macrophage nerve agent neuroblastoma cell neurotoxicity novel pesticide exposure public health relevance pyrethroid receptor expression receptor function respiratory smooth muscle response

项目摘要

DESCRIPTION (provided by applicant): We have demonstrated that in a guinea pig model, organophosphorus pesticides (OPs) cause airway hyperreactivity that is dose-related and associated with the functional loss of autoinhibitory muscarinic M2 receptors that normally limit acetylcholine release from parasympathetic nerves that innervate airway smooth muscle. We recently reported that sensitization to antigen alters the mechanisms underlying OP-induced airway hyperreactivity to involve IL-5-dependent mechanisms in the sensitized but not the non-sensitized guinea pig. How OPs cause neuronal M2 dysfunction in the non-sensitized animal is not known but our preliminary data indicate that this effect is not mediated by cholinesterase inhibition or direct antagonistic interactions with neuronal M2 receptors. Rather, OPs appear to influence neuronal M2 receptor function indirectly via effects on macrophages since depletion of macrophages using liposome-encapsulated clodronate protects against OP-induced airway hyperreactivity. It is our hypothesis that OPs activate macrophages to upregulate expression and release of inflammatory cytokines previously shown to cause M2 receptor dysfunction in various models of airway hyperreactivity. We propose four Aims to test this hypothesis. In Aim 1, we will use in vivo physiological measurements to confirm that macrophages mediate airway hyperreactivity caused by OPs and determine whether their role changes over time, as has been observed for eosinophils in ozone-induced airway hyperreactivity. Aim 2 will utilize macrophages isolated from bronchoalveolar lavage collected from OP-treated versus untreated guinea pigs guinea pigs to examine the effect of OPs on macrophage expression and release of inflammatory cytokines implicated in airway hyperreactivity. In Aim 3, we will use primary nerve cell cultures to determine whether OP- induced macrophage mediators interact with nerves directly to alter M2 receptor expression or function or the structural plasticity of nerves. Aim 4 will confirm the in vivo physiological relevance of OP-induced macrophage mediators identified in aims 2 and 3. Mechanistic studies are critical to developing preventive and therapeutic approaches for OP-induced airway hyperreactivity, which are likely to differ between sensitized (allergic) and non-sensitized individuals, and for determining the risks to human health posed by OP exposures. The public health implications of these studies are significant in light of the increasing prevalence of asthma, the wide spread exposure of humans and especially children to OPs and the credible threat of terrorist use of OP pesticides and nerve agents. PUBLIC HEALTH RELEVANCE: Recent epidemiological studies suggest a link between exposure to organophosphorus pesticides (OPs) and asthma. Our previous work confirms this link by demonstrating that OPs cause airway hyperreactivity, a major symptom of asthma, in a guinea pig model. The goal of this project is to elucidate the mechanism(s) by which OPs cause airway hyperreactivity, which will be critical to developing effective preventive and therapeutic approaches to OP-induced airway hyperreactivity. Given the documented widespread exposure to OPs not only in the U.S. but worldwide, and the credible threat of terrorist use of OPs, the proposed work is of significant public health relevance.

描述（由申请人提供）：我们已经证明，在豚鼠模型中，有机磷农药 (OP) 会引起气道高反应性，这种反应性与剂量相关，并与通常限制副交感神经释放乙酰胆碱的自抑制性毒蕈碱 M2 受体功能丧失有关。支配气道平滑肌。我们最近报道，对抗原的致敏改变了 OP 诱导的气道高反应性的机制，涉及致敏但非致敏豚鼠中的 IL-5 依赖性机制。 OP 如何在非致敏动物中引起神经元 M2 功能障碍尚不清楚，但我们的初步数据表明，这种效应不是通过胆碱酯酶抑制或与神经元 M2 受体的直接拮抗相互作用介导的。相反，OP 似乎通过对巨噬细胞的影响间接影响神经元 M2 受体功能，因为使用脂质体封装的氯膦酸盐消耗巨噬细胞可以防止 OP 诱导的气道高反应性。我们的假设是，OP 激活巨噬细胞上调炎症细胞因子的表达和释放，此前已证明这些细胞因子会在各种气道高反应性模型中导致 M2 受体功能障碍。我们提出四个目标来检验这一假设。在目标 1 中，我们将使用体内生理测量来确认巨噬细胞介导 OP 引起的气道高反应性，并确定其作用是否随时间而变化，正如在臭氧诱导的气道高反应性中观察到的嗜酸性粒细胞一样。目标 2 将利用从经 OP 处理的豚鼠和未处理的豚鼠收集的支气管肺泡灌洗液中分离出的巨噬细胞，来检查 OP 对巨噬细胞表达和与气道高反应性有关的炎症细胞因子释放的影响。在目标 3 中，我们将使用原代神经细胞培养物来确定 OP 诱导的巨噬细胞介质是否直接与神经相互作用，从而改变 M2 受体的表达或功能或神经的结构可塑性。目标 4 将确认目标 2 和 3 中确定的 OP 诱导的巨噬细胞介质的体内生理相关性。机制研究对于开发 OP 诱导的气道高反应性的预防和治疗方法至关重要，这些方法在致敏（过敏）和非敏感个体，以及确定有机磷暴露对人类健康造成的风险。鉴于哮喘患病率不断上升、人类（尤其是儿童）广泛接触有机磷农药，以及恐怖分子使用有机磷农药和神经毒剂的可信威胁，这些研究对公共卫生的影响意义重大。公共卫生相关性：最近的流行病学研究表明，接触有机磷农药 (OP) 与哮喘之间存在联系。我们之前的工作通过在豚鼠模型中证明 OP 引起气道高反应性（哮喘的主要症状）来证实这种联系。该项目的目标是阐明 OP 引起气道高反应性的机制，这对于开发针对 OP 引起的气道高反应性的有效预防和治疗方法至关重要。鉴于有记录的有机磷农药不仅在美国而且在全世界范围内都存在广泛接触，而且恐怖分子使用有机磷农药确实构成威胁，因此拟议的工作具有重要的公共卫生意义。