Organophosphates Modify Eosinophil and Nerve Interaction

描述（由申请人提供）：在许多疑似哮喘介质中，有机磷酸盐（OP）农药（如敌百虫）最近被认为可引起或加重哮喘。OP暴露是普遍存在的，并且可能在儿童中很重要，因为OP代谢物已在母乳和儿童尿液中报告。OP暴露可能通过增加嗜酸性粒细胞对气道神经的相互作用而使特应性个体易于发生气道高反应性。具体目的是检验假设1.在致敏豚鼠中，OP促进嗜酸性粒细胞释放主要碱性蛋白（MBP），导致M2毒蕈碱功能丧失和迷走神经刺激引起的支气管收缩增加。OP诱导肺神经中粘附分子ICAM-1和/或VCAM-1以及趋化因子eotaxin的表达，以及3. OP诱导嗜酸性粒细胞表达CD 11/CD 18、VLA-4和/或CCR 3，它们各自的反配体。将对暴露于对硫磷的致敏豚鼠进行处理以阻断MBP，并用于生理学研究以测量迷走神经刺激后支气管收缩的变化。将在分离的细胞中测量观察到的OP对嗜酸性粒细胞和神经的影响。

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.