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（OP）农药（如对硫磷）最近被认为会导致或加重哮喘。有机磷暴露是普遍存在的，在儿童中可能很重要，因为母乳和儿童尿液中有有机磷代谢物的报道。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，使特应性个体易发生气道高反应性。具体的目的是检验假设1。在致敏豚鼠中，OPs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，迷走神经刺激导致支气管收缩增加，2。2 . OPs诱导肺神经黏附分子ICAM-1和/或VCAM-1及趋化因子eotaxin的表达；OPs诱导CD11/CD18、VLA-4和/或CCR3等相应的配体在嗜酸性粒细胞上的表达。暴露于对偶磷的致敏豚鼠将被治疗阻断MBP，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OPs对嗜酸性粒细胞和神经的影响将在分离细胞中测量。

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.