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

• 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
• 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; 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

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（OPS）会导致气道高反应性，这与剂量相关，并与通常限制乙酰胆碱释放的乙酰胆碱释放的副交感神经会释放的均质性交感神经会平滑肌的功能丧失相关。我们最近报道，对抗原的敏化改变了呼吸道诱导的基础机制，使气道高反应性涉及IL-5依赖性机制，而不是敏化的，但不涉及非敏化的豚鼠。 OPS如何引起非敏化动物中神经元M2功能障碍尚不清楚，但我们的初步数据表明，这种作用不是通过胆碱酯酶抑制或与神经元M2受体直接拮抗相互作用介导的。相反，OPS似乎通过对巨噬细胞的影响间接影响神经元的M2受体功能，因为使用脂质体封装的氯膦酸盐可预防OP诱导的气道高反应性。我们的假设是，OPS激活巨噬细胞以上调和释放的炎症细胞因子的表达和释放，以前显示在各种气道高反应性中引起M2受体功能障碍。我们提出了四个旨在检验这一假设的目标。在AIM 1中，我们将使用体内生理测量值来确认巨噬细胞介导OP引起的气道过度反应性，并确定其作用是否随着时间的流逝而变化，正如臭氧诱导的气道高反应性中的嗜酸性粒细胞所观察到的那样。 AIM 2将利用从从运算处理的和未处理的豚鼠豚鼠中收集的支气管肺泡灌洗中分离出来的巨噬细胞，以检查OPS对巨噬细胞表达的影响以及与气道高反应性有关的炎症细胞因子的释放。在AIM 3中，我们将使用原代神经细胞培养物来确定接合巨噬细胞介体是否直接与神经相互作用以改变M2受体表达或功能或神经的结构可塑性。 AIM 4将确认在AIM 2和3中确定的操作诱导的巨噬细胞介体的体内生理相关性。机械研究对于开发运算诱导的气道高反应性的预防和治疗方法至关重要，这可能会在敏感（过敏）和非敏感的个体和确定人类健康的风险之间存在差异（敏感性）（过敏）之间的差异。鉴于哮喘的患病率不断增长，人类，尤其是儿童对行动的蔓延，以及恐怖分子使用OP农药和神经剂的可靠威胁，这些研究的公共卫生影响很大。 公共卫生相关性：最近的流行病学研究表明，暴露于有机磷农药（OP）和哮喘之间存在联系。我们以前的工作通过证明OPS在豚鼠模型中引起气道高反应性（哮喘的主要症状）来证实这种联系。该项目的目的是阐明OPS引起气道高反应性的机制，这对于开发有效的预防和治疗方法至关重要，以实现OP诱导的气道高反应性。鉴于不仅在美国，而且在全球范围内对OPS的广泛接触以及对行动使用恐怖主义使用的可信威胁，拟议的工作具有很大的公共卫生相关性。