Organophosphates Modify Eosinophil and Nerve Interaction

描述(由申请人提供)：在许多可疑的哮喘介质中，有机磷(OP)杀虫剂，如对硫磷，最近被认为与引起或加剧哮喘有关。OP暴露在儿童中是普遍存在的，而且可能在儿童中很重要，因为已有报道在母乳和儿童尿液中发现OP代谢物。OP暴露可能通过增加嗜酸性粒细胞与呼吸道神经的相互作用而使特应性个体易患呼吸道高反应性。其具体目的是验证以下假设：1.OP促进嗜酸性粒细胞释放主要碱性蛋白(MBP)，导致M_2毒碱功能丧失，增强对迷走神经刺激的支气管收缩；2.OP诱导肺神经表达黏附分子ICAM-1和/或VCAM-1以及趋化因子Eoaxin；3.OP诱导嗜酸性粒细胞表达CD11/CD18、VLA-4和/或CCR3。致敏的对硫磷暴露的豚鼠将接受阻断MBP的治疗，并用于生理研究，以测量迷走神经刺激后支气管收缩的变化。观察到的有机磷农药对嗜酸性粒细胞和神经的影响将在分离的细胞中进行测量。

DESCRIPTION (provided by applicant): Of the many suspected mediators of asthma, organophosphate (OP) pesticides such as parathion are recently implicated to cause or excacerbate asthma. OP exposure is ubiquitous and probably significant in children since OP metabolites have been reported in breast milk and children's urine. OP exposure may predispose atopic individuals to airway hyperreactivity through increased interactions of eosinophils on the airway nerves. The specific aims are to test the hypothesis that 1. OPs promote the release of major basic protien (MBP) from eosinophils leading to a loss of M2 muscarinic function and an increase in bronchoconstriction to vagal stimulation in sensitized guinea pigs, 2. OPs induce the expression of the adhesion molecules ICAM-1 and/or VCAM-1 and the chemotactant eotaxin in lung nerves, and 3. OPs induce the expression of CD11/CD18, VLA-4, and/or CCR3, the respective counerligands, on the eosinophils. Sensitized, parathion-exposed guinea pigs will be treated to block MBP and used in physiological studies to measure changes in bronchocontstriction after vagal stimulation. The observed effects of OPs on eosinophils and nerves will be measured in isolated cells.