ETHANOL AND ACETALDEHYDE-ALTERED CILIARY MOTILITY

酗酒者患肺部疾病的几率增加 部分原因是与酒精相关的肺宿主防御功能改变 毒性。酗酒者也有很强的吸烟倾向。 很重。一种主要的呼吸道防御功能在这两种情况下受损 酒精摄入和吸烟是粘液纤毛的清除 系统依赖于纤毛的协调跳动，即线 航空公司。粘液纤毛损伤的一种可能机制 酒精摄入和吸烟都是乙醛接触，因为 乙醛是在乙醇的新陈代谢过程中产生的，既有 肝脏和局部呼吸道中也发现了大量的 在香烟烟雾的汽相中。我们实验室的最新研究 提示乙醇通过一氧化氮刺激纤毛运动 依赖机制。更多的发现表明，这不依赖于 作用机制对乙醛损伤尤为敏感。在这方面，我们 假设：乙醇和乙酰丙二醛改变NO依赖的纤毛 呼吸道上皮细胞的运动性。 为了验证这一假设，我们将围绕四个方面进行实验 具体目标： 1)研究乙醇对呼吸道上皮细胞一氧化氮合酶的影响 一氧化氮合酶活性与乙醇诱导纤毛运动的关系 改变；2)确定乙醇如何刺激纤毛运动信号 评估纤毛中连续步骤的转导途径 激活途径；3)确认和表征 乙醛对NO依赖性纤毛运动的影响；4)测定 乙醛抑制NO依赖性兴奋作用的机制(S) 纤毛运动。 酒精和吸烟相关的呼吸系统疾病对社会的影响 是巨大的。我们在这项建议中概述的研究将探讨 乙醇和乙醛促进NO依赖的新机制 分别损害睫状体功能。建立这两个机制 其中乙醇似乎刺激纤毛，乙醛损害纤毛 在呼吸道细胞中的功能将提供有意义的洞察力 酒精摄入和吸烟在支气管炎的发病机制中起着作用， 肺炎和肺癌。

Alcoholics have an increased incidence of pulmonary diseases that are in part due to altered lung host defense functions related to alcohol toxicity. There is also a strong tendency for alcoholics to smoke heavily. A major airway defense function that is impaired during both alcohol ingestion and cigarette smoking is the mucociliary clearance system which is dependent on the coordinated beating of cilia that line the airways. One possible mechanism of mucociliary impairment common to both alcohol ingestion and smoking is acetaldehyde exposure since acetaldehyde is produced during the metabolism of ethanol, both by the liver and locally in the airways, and is also found in significant amounts in the vapor phase of cigarette smoke. Recent studies from our lab indicate that ethanol stimulates ciliary motility through a nitric-oxide dependent mechanism. Additional findings indicate that this NO-dependent mechanism is especially sensitive acetaldehyde injury. In this context we hypothesize that: ETHANOL AND ACETALDEHDYE ALTER NO-DEPENDENT CILIARY MOTILITY IN AIRWAY EPITHELIA. To test this hypothesis we will perform experiments focused around four specific aims: 1) Characterize the effects of ethanol on airway epithelial NO synthases (NOS) and correlate NOS activation with ethanol-induced ciliary motility changes; 2) Determine how ethanol stimulates the ciliary motility signal transduction pathway by evaluating sequential steps in the cilia activation pathway; 3) Confirm and characterize the effects of acetaldehyde on NO-dependent changes in ciliary motility; 4) Determine the mechanisms(s) by which acetaldehyde impairs NO-dependent stimulation of ciliary motility. The impact of alcohol and smoking-related respiratory illnesses on society is immense. The studies we have outlined in this proposal will explore a novel NO-dependent mechanism by which ethanol and acetaldehyde enhance or impair ciliary function, respectively. Establishing both the mechanisms by which ethanol appears to stimulate and acetaldehyde impairs ciliary function in airways cells will provide meaningful insight into the roles alcohol ingestion and smoking play in the pathogenesis of bronchitis, pneumonia and lung cancer.