Asthma Exacerbation by Organophosphate Pesticides

描述（由申请人提供）：我们已发表的论文证明，有机磷（OP）诱导气道高反应性，其与剂量相关，与抑制性神经元M2受体功能丧失相关，通常限制乙酰胆碱释放，并且在显著低于抑制乙酰胆碱酯酶的剂量下发生。在这里，我们表明，致敏的动物（致敏抗原，但从来没有挑战抗原）是显着更敏感的OP比非致敏对照。0.001 mg/kg的OP双磷酸钠在非致敏豚鼠中未引起高反应性，但在致敏动物中使迷走神经诱导的支气管收缩加倍。较高剂量的OP确实会影响非致敏动物，但对致敏动物的影响显著更大。此外，我们发现OP诱导的高反应性的机制并不依赖于非致敏动物的嗜酸性粒细胞，而是在致敏后转换为需要嗜酸性粒细胞。我们已经开发了一个模型，嗜酸性粒细胞神经相互作用，包括积极招聘和嗜酸性粒细胞粘附副交感神经，然后激活和释放嗜酸性粒细胞主要碱性蛋白，这是一种内源性拮抗剂的M2受体。我们的假设是，OP诱导的高反应性在致敏动物介导的OP影响趋化因子和粘附分子，增强嗜酸性粒细胞的招聘神经，也OP诱导嗜酸性粒细胞活化。我们将测试这在体外人类和豚鼠副交感神经和在豚鼠体内。有四个具体目标：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）。目的2将检查OP改变趋化因子、其受体和粘附分子表达的能力，并在细胞水平上改变嗜酸性粒细胞-神经相互作用。目标3将检查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，人体暴露于OP的程度很高，鉴于80%以上的哮喘儿童也对抗原敏感，这些研究可能直接影响被认为安全的OP暴露水平，并提供暴露后干预的目标。

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.