SITES OF ACTION AND ROLE OF MEDIATORS IN ASTHMA

组胺和过敏反应的慢反应物质（ 白三烯C4、D4和E4）是可逆气道的重要介质 阻塞性哮喘 在哮喘中观察到的气道阻塞是 很大程度上是由大气道的支气管痉挛， 以及支气管痉挛和小气道中的粘液分泌过多。 我们 假设组胺主要作用于大气道，或 均匀地分布在整个肺中，而LT主要作用于 较小的气道。 此外，我们假设， 粘液分泌过多导致哮喘气道阻塞， 小气道中粘液纤毛运输的改变。 为了检验这些假设，我们建议：1）比较激发剂量 优先沉积的组胺和LTD 4气溶胶在大， 健康和哮喘受试者的较小气道;以及2）比较 激发剂量组胺和LTD 4对粘膜纤毛转运的影响 在健康和哮喘受试者中。 我们打算进行的实验 将采用气溶胶沉积、肺粘膜纤毛 清除，和气管粘膜纤毛运输在我们的实验室开发。 调解员的作用部位将通过四个独立的评估 介质激发：2例伴有中心沉积组胺或LTD 4， 其中两个患有外周沉积的组胺或LTD 4。 介质气溶胶， 由超声波雾化器（6 μ M直径）产生，将 优选使用两种不同的呼吸模式沉积。 到 确定肺部的介质剂量，每个受试者将吸入6 μ M Tc-99 m标记的Fe 2 O3的水性气溶胶，以与介体相同的方式 在挑战之前进行喷雾。 总肺沉积和局部肺沉积将 使用气溶胶光度法、闪烁计数和伽马射线测定 照相机成像。 介质对粘膜纤毛转运的影响将使用6 μ m的 Tc-99 m标记的Fe 2 O3气溶胶以影响外周 证词 在放射性气溶胶沉积后，立即进行预定的 组胺或LTD 4或盐水气雾剂的激发剂量将被 管理。 实验对象将被放置在伽马照相机前 一个多探测器探头在他脖子前放置了4.7小时 肺粘液纤毛清除率和气管粘液纤毛清除率的测量 运输率。

Histamine and slow reacting substance of anaphylaxis (a mixture of leukotrienes C4, D4, and E4) are important mediators of reversible airways obstruction in asthma. The airways obstruction observed in asthma is caused in large part by a combination of bronchospasm in the large airways, and bronchospasm and mucus hypersecretion in the smaller airways. We hypothesize that histamine acts primarily in the large airways, or uniformly throughout the lungs, whereas the LT's act primarily in the smaller airways. Furthermore, we hypothesize that the contribution of mucus hypersecretion to airways obstruction in asthma arises from alterations of mucociliary transport in the smaller airways. To test these hypotheses we propose to: 1) compare the provocation doses of preferentially deposited histamine and LTD4 aerosol in the large and smaller airways of healthy and asthmatic subjects; and 2) compare the effects of provocation doses of histamine and LTD4 on mucociliary transport in healthy and asthmatic subjects. The experiments we propose to conduct will employ measurement techniques of aerosol deposition, lung mucociliary clearance, and tracheal mucociliary transport developed in our laboratory. The sites of action of the mediators will be assessed with four separate mediator challenges: two with centrally deposited histamine or LTD4, and two with peripherally deposited histamine or LTD4. The mediator aerosols, generated by an ultrasonic nebulizer, (6 MuM diameter), will be preferentially deposited using two different breathing patterns. To determine mediator dose to the lungs each subject will inhale a 6 Mum aqueous aerosol of Tc-99m-labelled Fe2O3 in the same manner as the mediator aerosol prior to challenge. Total and regional lung deposition will be determined using aerosol photometry, scintillation counting, and gamma camera imaging. Mediator effects on mucociliary transport will be determined using a 6 Mum Tc-99m-labelled Fe2O3 aerosol inhaled in a manner to effect peripheral deposition. Immediately after radioaerosol deposition, a predetermined challenge dose of either histamine or LTD4, or a saline aerosol will be administered. The subject will then be placed in front of a gamma camera and a multidetector probe placed in front of his neck for a 4.7 hour measurement of lung mucociliary clearance and tracheal mucociliary transport rate.