Asthma Exacerbation by Organophosphate Pesticides

我们已发表的论文表明，有机磷（OP）诱导气道高反应性， 剂量相关，与通常限制乙酰胆碱的抑制性神经元M2受体功能丧失相关 在剂量显著低于抑制乙酰胆碱酯酶的药物时，会发生这种情况。在此我们表明 致敏动物（对抗原致敏但从未用抗原激发） 对OP的敏感性高于非致敏对照。0.001mg/kg的OP钙离子没有引起高反应性 在非致敏豚鼠中，但在致敏动物中，它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。 动物此外，我们表明OP诱导的高反应性的机制不依赖于 在非致敏动物中，嗜酸性粒细胞减少，但在致敏后转为需要嗜酸性粒细胞。我们有 开发了嗜酸性粒细胞-神经相互作用的模型，包括嗜酸性粒细胞的主动募集和粘附 嗜酸性粒细胞向副交感神经传递，随后激活和释放嗜酸性粒细胞主要碱性蛋白 它是M2受体的内源性拮抗剂。我们假设OP诱导的高反应性 在致敏动物中，由影响趋化因子和粘附分子的OP介导， 增强嗜酸性粒细胞向神经的募集，以及OP诱导的嗜酸性粒细胞活化。我们将在 体外人和豚鼠副交感神经和豚鼠体内。有四个具体目标： 我们将测试对OP的敏感性增加是否扩展到OP类，并将包括其他非OP类。 杀虫剂作为对照（AIM 1）。目的2将检查OP改变趋化因子表达的能力， 因子，其受体和粘附分子，并在细胞水平上改变嗜酸性粒细胞-神经相互作用。 目的3将检查OP如何激活嗜酸性粒细胞，目的4将确定生理相关性 目标2和目标3中确定的体内途径。在美国，人类暴露于OP的情况很严重， 在世界范围内，鉴于超过80%的哮喘儿童也对抗原过敏，这些研究 可能直接影响被认为是安全的OP暴露水平，并提供干预目标， exposure.

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. 0.001mg/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 parasymapthetic 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 recruitement 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 (aim1). 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.