Asthma Exacerbation by Organophosphate Pesticides

我们已经发表的论文表明，有机磷(OP)诱导呼吸道高反应性，即 与剂量相关，与通常限制乙酰胆碱的抑制神经元M2受体功能丧失有关 释放，并且发生在显著低于那些抑制乙酰胆碱酯酶的剂量。我们在这里展示 致敏的动物(对某种抗原敏感，但从未被抗原攻击)明显更多 对有机磷农药的敏感性高于非致敏对照。0.01 mg/kg的OP对硫磷不会引起高反应性 在非致敏豚鼠中，但在致敏动物中迷走神经诱导的支气管收缩增加一倍。 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要大得多。 动物。此外，我们还证明了OP诱导高反应性的机制不依赖于 未致敏动物体内的嗜酸性粒细胞，但致敏后转为需要嗜酸性粒细胞。我们有 建立了嗜酸性粒细胞-神经相互作用的模型，包括主动招募和黏附 嗜酸性粒细胞激活和释放嗜酸性粒细胞主要碱性蛋白至副交感神经 这是M2受体的内源性拮抗剂。我们的假设是OP诱导的高反应性 在致敏动物中是由影响趋化因子和黏附分子的OP介导的， 增强嗜酸性粒细胞对神经的再刺激作用，也可诱导嗜酸性粒细胞活化。我们将对此进行测试 离体人和豚鼠副交感神经及活体豚鼠。具体目标有4个： 我们将测试对OP的敏感度是否会扩展到OP类，并将包括其他非OP类 杀虫剂作为对照(AIM1)。目标2将检测OPs改变趋化表达的能力 因子、它们的受体和黏附分子在细胞水平上改变嗜酸性粒细胞与神经的相互作用。 目标3将检查OPs如何激活嗜酸性粒细胞，目标4将确定生理相关性 体内AIMS 2和AIMS 3中发现的通路。在美国，人类对有机磷农药的接触很大 在世界范围内，鉴于超过80%的哮喘儿童也对抗原敏感，这些研究 可直接影响被认为是安全的OP暴露水平，并提供干预目标 曝光。

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.