Asthma Exacerbation by Organophosphate Pesticides

描述（由申请人提供）：我们已经发表的论文表明，有机磷酸盐（OPs）诱导气道高反应性，这与剂量相关，与通常限制乙酰胆碱释放的抑制性神经元M2受体功能的丧失有关，并且在明显低于抑制乙酰胆碱酯酶的剂量时发生。在这里，我们发现致敏动物（对抗原致敏但从未被抗原激发）对OPs的敏感性明显高于未致敏的对照组。0.001 mg/kg的OP对硫磷在未致敏的豚鼠中没有引起高反应性，但在致敏动物中，它使迷走神经诱导的支气管收缩加倍。高剂量的OPs对未致敏动物的影响更大，对致敏动物的影响更大。此外，我们发现OP诱导的高反应性的机制不依赖于非致敏动物的嗜酸性粒细胞，但在致敏后转而需要嗜酸性粒细胞。我们已经建立了一个嗜酸性粒细胞-神经相互作用的模型，包括嗜酸性粒细胞主动募集和粘附到副交感神经，随后是嗜酸性粒细胞主要碱性蛋白的激活和释放，这是一种内源性的M2受体拮抗剂。我们的假设是OP诱导致敏动物的高反应性是由OP影响趋化因子和粘附分子介导的，这些因子和粘附分子增强了嗜酸性粒细胞向神经的募集，OP也诱导了嗜酸性粒细胞的活化。我们将在体外测试非人和豚鼠副交感神经以及在豚鼠体内测试。有4个具体目标：我们将测试对OPs的敏感性增加是否会扩展到OP类，并将其他非OP杀虫剂作为对照（目标1）。目的2将研究OPs在细胞水平上改变趋化因子、其受体和粘附分子表达以及改变嗜酸性粒细胞-神经相互作用的能力。目的3将研究OPs如何激活嗜酸性粒细胞，目的4将确定目的2和目的3中确定的生理相关途径。在美国和世界范围内，人类暴露于OP的量很大，考虑到超过80%的哮喘儿童也对抗原敏感，这些研究可以直接影响被认为是安全的OP暴露水平，并为暴露后的干预提供目标。

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.