ETHANOL AND ACETALDEHYDE-ALTERED CILIARY MOTILITY

酒精中毒者肺部疾病的发病率增加， 部分原因是与酒精有关的肺部宿主防御功能改变 毒性 酗酒者吸烟的倾向也很强 很重。 一个主要的气道防御功能，是受损的过程中， 酒精摄入和吸烟是粘膜纤毛清除 系统依赖于纤毛的协调跳动， 呼吸道 一种可能的机制，粘膜纤毛损害共同的， 酒精摄入和吸烟都是乙醛暴露， 乙醛是在乙醇的代谢过程中产生的， 肝脏和局部的气道，也发现了大量的 在香烟烟雾的气相中。 我们实验室最近的研究 表明乙醇通过一氧化氮刺激纤毛运动 依赖机制 其他研究结果表明，这种NO依赖性 机制是特别敏感的乙醛损伤。 在这方面我们 假设：乙醇和乙醛可改变非依赖性纤毛 呼吸道上皮的运动性。 为了验证这一假设，我们将进行实验，重点围绕四个 具体目标： 1)表征乙醇对气道上皮NO还原酶的影响 (NOS)并将NOS激活与乙醇诱导的纤毛运动相关 2）确定乙醇如何刺激纤毛运动信号 通过评估纤毛中的顺序步骤来分析转导途径 激活途径; 3）确认和表征 乙醛对睫状体运动的NO依赖性变化的影响; 4）确定 乙醛损害NO依赖性刺激的机制 纤毛运动 与酒精和吸烟有关的呼吸道疾病对社会的影响 是巨大的。 我们在本提案中概述的研究将探讨 一种新的NO依赖性机制，通过该机制，乙醇和乙醛增强或 分别损害纤毛功能。 建立两个机制 乙醇似乎刺激纤毛，乙醛损害纤毛 气道细胞的功能将提供有意义的见解， 酒精摄入和吸烟在支气管炎的发病机制中起作用， 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.