POLLUTANT INDUCED MUCOCILIARY DYSFUNCTION IN THE AIRWAYS

此前已有研究表明，短期和长期暴露于 气态污染物会改变呼吸道的粘膜功能。其作用机制 与粘液纤毛清除相关的抑郁的潜在原因是 部分阐明了。具体地说，已经表明， 粘膜分泌而不是原发纤毛功能障碍是原因 来弥补这个缺陷。然而，目前尚不清楚观察到的功能 变化是由污染物对粘液纤毛的直接影响引起的 仪器或间接地由伴随的呼吸道炎症来模拟到 先前显示的呼吸道炎症在污染物诱导中的作用 呼吸道高反应性。因此，这项建议的目的是 在绵羊身上确定是否1)短期的胃粘膜功能受损 低水平的臭氧暴露(0.5-1ppm，持续2小时)与白细胞有关 进入呼吸道，2)防止白细胞的迁移 防止污染物引起的粘膜功能障碍，3)粘膜功能障碍 与炎症介质有关，4)新生儿的呼吸道更脆弱 对污染物引起的粘膜功能障碍的影响要比成人呼吸道大，5) 污染物引起的粘膜功能障碍改变中央细菌的清除 呼吸道和细菌清除是否因炎症而改变 回应。这些研究将在羔羊和成年绵羊身上进行， 重点放在气管上。粘膜功能将在活体内通过 用放射照相技术测定粘液纤毛转运 双气泡法检测气道壁水分含量 浮肿的形成。呼吸道炎症将通过气管灌洗进行评估 和活检，以及化学介体在灌洗中的作用 流质，并使用适当的拮抗剂。一种细菌气雾剂将是 用来确定活细菌在气管中的持久性。至 抑制炎症反应，Pluronic F-68，一种有效的 将使用白细胞迁移。我们期望这些研究能勾勒出 炎症在臭氧损伤粘膜功能中的作用。这个 这些结果可能为污染物的药理修饰提供依据 引起粘液纤毛功能障碍。

It has been previously shown that short-term and long-term exposures to gaseous pollutants alter mucosal function in the airways. The mechanisms underlying the associated depression in mucociliary clearance have been partially elucidated. In particular, it has been shown that changes in mucosal secretion rather than primary ciliary dysfunction are responsible for this defect. However, it is not known if the observed functional changes are caused by a direct effect of the pollutant on the mucociliary apparatus or indirectly by the concomitant airway inflammation in analog to the previously shown role of airway inflammation in pollutant induced airway hyperreactivity. The purpose of this proposal is therefore to determine in sheep if 1) the impairment of mucosal function by short-term low-level O3 exposure (0.5-1 ppm for 2 hours) is associated with leukocytes influx into the airway, 2) the prevention of leukocyte migration also prevents pollutant induced mucosal dysfunction, 3) mucosal dysfunction is related to inflammatory mediators, 4) the newborn airway is more vulnerable to pollutant induced mucosal dysfunction than the adult airway, and 5) pollutant induced mucosal dysfunction alters bacterial clearance in central airways and if the bacterial clearance is modified by the inflammatory response. The studies will be carried out in lambs and adult sheep and focus on the trachea. Mucosal function will be assessed in vivo by the determination of mucociliary transport with a radiographic technique and airway wall water content using a double gas bolus method to detect mucosal edema formation. Airway inflammation will be assessed by tracheal lavage and biopsy, and the role of chemical mediators by mediator assay in lavage fluid, and the use of appropriate antagonists. A bacterial aerosol will be used to determine the persistence of viable bacteria in the trachea. To suppress the inflammatory response, pluronic F-68, a potent inhibitor of leukocyte migration will be used. We expect these studies to delineate the role of inflammation in the impairment of mucosal function by O3. The results might form the basis for pharmacologic modification of pollutant induced mucociliary dysfunction.