SITES OF ACTION AND ROLE OF MEDIATORS IN ASTHMA

组胺和过敏性慢反应物质(组胺的混合物 白三烯C4、D4和E4)是可逆性呼吸道的重要介质 哮喘中的梗阻。在哮喘中观察到的呼吸道阻塞是 在很大程度上是由大呼吸道的支气管痉挛引起的， 小气道出现支气管痉挛和粘液高分泌。我们 假设组胺主要在大气道起作用，或者 在整个肺中均匀分布，而LT的行为主要在 较小的航空公司。此外，我们假设， 哮喘引起的呼吸道阻塞粘液高分泌 小气道内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LTD4气溶胶在大型和 健康受试者和哮喘受试者较小的呼吸道；以及2)比较 组胺和LTD4的激发剂量对粘液纤毛转运的影响 在健康和哮喘受试者中。我们计划进行的实验 将采用气溶胶沉积、肺粘液纤毛的测量技术 清除和气管粘液纤毛运输是我们实验室开发的。 调解人的行动地点将用四个单独的 中介人挑战：两人中枢性沉积组胺或LTD4，以及 两人外周沉积组胺或LTD4。介体气雾剂， 由超声波雾化器(直径6微米)产生的 优先使用两种不同的呼吸模式存放。至 确定肺部介质剂量每个受试者将吸入6毫升 以与介体相同的方式标记三氧化二铁的气雾剂 挑战前的气雾剂。总肺和区域肺沉积将是 使用气溶胶测光、闪烁计数和伽马测量 相机成像。 粘液纤毛转运的介体作用将使用6个Mum来确定 以影响外周的方式吸入TC-99M标记的Fe2O3气雾剂 证词。在放射性气溶胶沉积之后，立即预定的 挑战剂量的组胺或LTD4，或者生理盐水气雾剂 管理。然后，受试者将被放置在伽马相机前面 在他的脖子前放置了一个多探测器探头4.7小时 肺粘液纤毛清除量和气管粘液纤毛清除量的测定 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.