Asthma Exacerbation by Organophosphate Pesticides

有机磷农药加剧哮喘

• 批准号: 7213910
• 负责人: ALLISON Deborah FRYER
• 金额: $ 34.58万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-12-06 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7213910
• 关键词: Acetylcholine; Acetylcholinesterase; Adhesions; Affect; Animals; Antigens; Asthma; Bronchoconstriction; Cavia; Cell Adhesion Molecules; Chemotactic Factors; Child; Class; Cultured Cells; Data; Dose; Eosinophil Major Basic Protein; Exposure to; Functional disorder; Human; In Vitro; Individual; Insecticides; Intervention; Lung; Mediating; Modeling; Muscarinic M2 Receptor; Nerve; Neurons; Organophosphates; Paper; Parathion; Pathway interactions; Pesticides; Physiological; Population; Prevalence; Proteins; Publishing; Recruitment Activity; Testing; United States; airway hyperresponsiveness; antigen challenge; atopy; eosinophil; exposed human population; in vivo; novel; organophosphorus insecticide; receptor; receptor function; response; stressor; toxic organophosphate insecticide exposure

DESCRIPTION (provided by applicant): We have published papers demonstrating that organophosphates (OPs) induce airway hyperreactivity that is dose related, associated with loss of inhibitory neuronal M2 receptor function that normally limit acetylcholine release, and occurs at doses significantly lower than those that inhibit acetylcholinesterase. Here, we show that sensitized animals (sensitized to an antigen but never challenged with antigen) are significantly more sensitive to OPs than non sensitized controls. 0.001 mg/kg of the OP parathion did not cause hyperreactivity in non-sensitized guinea pigs but it doubled vagally-induced bronchoconstriction in sensitized animals. Higher doses of OPs, that did affect non sensitized animals, had a significantly greater effect in sensitized animals. In addition, we show that the mechanism for OP induced hyperreactivity does not depend on eosinophils in non sensitized animals, but is switched to require eosinophils after sensitization. We have developed a model for eosinophil-nerve interactions that includes active recruitment and adhesion of eosinophils to parasympathetic nerves followed by activation and release of eosinophil major basic protein that is an endogenous antagonist for the M2 receptors. It is our hypothesis that OP-induced hyperreactivity in sensitized animals is mediated by OPs affecting chemotactic factors and adhesion molecules that enhance eosinophil recruitment to nerves, and also OP induced eosinophil activation. We will test this in vitro inhuman and guinea pig parasympathetic nerves and in vivo in guinea pigs. There are 4 specific aims: We will test whether increased sensitivity to OPs extends to the OP class and will include other non OP insecticides as controls (aim 1). Aim 2 will examine the ability of OPs to alter expression of chemotactic factors, their receptors and adhesion molecules and alter eosinophil-nerve interactions at a cellular level. Aim 3 will examine how OPs activate eosinophils and aim 4 will determine the physiological relevance pathways identified in aims 2 and 3 in vivo. Human exposures to OPs is great in the United States and worldwide, given that more than 80% of children with asthma are also sensitized to antigen, these studies could directly impact levels of OP exposure considered safe and provide targets for intervention after exposure.

描述（由申请人提供）：我们发表的论文证明，有机磷酸酯 (OP) 会诱发与剂量相关的气道高反应性，与通常限制乙酰胆碱释放的抑制性神经元 M2 受体功能的丧失相关，并且发生的剂量明显低于抑制乙酰胆碱的剂量乙酰胆碱酯酶。在这里，我们发现致敏动物（对抗原敏感但从未受到抗原攻击）对 OP 的敏感度明显高于非致敏对照。 0.001 mg/kg OP 对硫磷不会引起非致敏豚鼠的高反应性，但会使致敏动物迷走神经诱导的支气管收缩加倍。较高剂量的有机磷农药确实会影响非致敏动物，但对致敏动物的影响明显更大。此外，我们发现OP诱导高反应性的机制并不依赖于非致敏动物中的嗜酸性粒细胞，而是在致敏后转为需要嗜酸性粒细胞。我们开发了嗜酸性粒细胞-神经相互作用的模型，其中包括嗜酸性粒细胞主动募集和粘附到副交感神经，然后激活和释放嗜酸性粒细胞主要碱性蛋白，该蛋白是 M2 受体的内源性拮抗剂。我们的假设是，致敏动物中 OP 诱导的高反应性是由影响趋化因子和粘附分子的 OP 介导的，这些分子增强了嗜酸性粒细胞向神经的募集，同时也是 OP 诱导的嗜酸性粒细胞活化。我们将在体外测试人类和豚鼠的副交感神经，并在体内测试豚鼠的副交感神经。有 4 个具体目标： 我们将测试对 OP 的敏感性增加是否延伸到 OP 类别，并将包括其他非 OP 杀虫剂作为对照（目标 1）。目标 2 将检查 OP 改变趋化因子、其受体和粘附分子表达以及在细胞水平上改变嗜酸性粒细胞-神经相互作用的能力。目标 3 将研究 OP 如何激活嗜酸性粒细胞，目标 4 将确定目标 2 和 3 中确定的体内生理相关途径。在美国和世界范围内，人类对 OP 的暴露量很大，考虑到超过 80% 的哮喘儿童也对抗原敏感，这些研究可能会直接影响被认为安全的 OP 暴露水平，并为暴露后的干预提供目标。