ETHANOL AND ACETALDEHYDE-ALTERED CILIARY MOTILITY

乙醇和乙醛改变了纤毛运动

• 批准号: 2894025
• 负责人: Joseph H Sisson
• 金额: $ 19.15万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-03-01 至 2000-09-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2894025
• 关键词: acetaldehyde; adduct; biological signal transduction; cilium /flagellum motility; dynein ATPase; ethanol; laboratory rat; metabolism; nitric oxide synthase; respiratory airway clearance; respiratory disorder; respiratory epithelium; respiratory function; smoking; toxicology; vapor

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.

酒精中毒的发生率增加了 部分是由于与酒精有关的肺部宿主防御功能改变的部分 毒性。 酗酒者也有强烈的趋势 沉重。 两者期间都受损的主要气道防御功能 酒精摄入和吸烟是粘膜毛的清除 依赖于纤毛的协调跳动的系统 呼吸道。 粘毛损伤的一种可能机制 饮酒和吸烟都是乙醛暴露，因为 乙醛在乙醇的代谢过程中产生，均由 肝脏和局部在气道中，也有大量的 在香烟烟雾的蒸气阶段。 我们实验室的最新研究 表明乙醇通过一氧化物刺激睫状运动性 依赖机制。 其他发现表明这种无依赖性 机制特别是敏感的乙醛损伤。 在这种情况下，我们 假设是：乙醇和乙醇改变无依赖性睫状 气道上皮的运动。 为了检验该假设，我们将执行聚焦于四个的实验 具体目的： 1）表征乙醇对气道上皮无合酶的影响 （NOS）并将NOS激活与乙醇诱导的睫状运动相关联 变化； 2）确定乙醇如何刺激睫状运动信号 通过评估纤毛中的顺序步骤来转导途径 激活途径； 3）确认并表征 乙醛无依赖性纤毛运动的变化； 4）确定 乙醛损害无依赖性刺激的机制 睫状运动。 酒精和与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索 乙醇和乙醛增强或 分别损害睫状功能。 建立这两个机制 乙醇似乎会刺激和乙醛会损害睫状 气道单元中的功能将为角色提供有意义的见解 在支气管炎的发病机理中，酒精摄入和吸烟发挥作用， 肺炎和肺癌。