ACETALDEHYDE-MEDIATED BRONCHIAL CILIA DYSFUNCTION

乙醛介导的支气管纤毛功能障碍

• 批准号: 2044840
• 负责人: Joseph H Sisson
• 金额: $ 9.83万
• 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 1996-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2044840
• 关键词: acetaldehyde; adenylate kinase; alcoholic beverage consumption; alcoholism /alcohol abuse; bronchial mucus; bronchomotion; cell free system; cilium; covalent bond; drug interactions; drug metabolism; drug receptors; dynein ATPase; enzyme inhibitors; laboratory rat; microtubules; polymerization; respiratory airway clearance; respiratory disorder; respiratory function; tobacco abuse; toxicology; tubulin

APPLICANT'S ABSTRACT: Alcoholics have an increased incidence of pulmonary diseases that are in part due to altered lung host defense functions related to alcohol toxicity and 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. 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. This is important because acetaldehyde is a highly reactive molecule that has been recognized as a significant toxin in biologic systems related to its ability to covalently bind to reactive protein residues. Preliminary experiments have demonstrated the influence of acetaldehyde on bronchial epithelial cell cilia. These studies established that acetaldehyde is directly toxic to ciliated airway epithelial cells causing cilia slowing or paralysis, inhibits cilia dynein ATPase activity, and binds to cilia proteins critical for motility especially dynein and tubulin. It is hypothesized, therefore, that: Acetaldehyde impairs airway cilia function by binding to critical cilia proteins, including dynein and tubulin, in concentrations encountered during alcohol ingestion and cigarette smoking. To test this hypothesis the following specific aims are proposed: 1) Assess the ability of acetaldehyde to bind to axonemal dynein and tubulin and impair the ATPase activity of dynein. These experiments will measure stoichiometric and competitive acetaldehyde binding to and functional impairment of purified cilia dynein and tubulin. 2) Elucidate the mechanism(s) by which acetaldehyde binding impairs the interaction of axonemal dynein with tubulin and microtubules. These experiments will examine acetaldehyde's effect on dynein's ability to enhance microtubule polymerization and translocate microtubules in a cell-free system. 3) Assess the importance of acetaldehyde exposure as a cause of cilia dysfunction in the setting of alcohol and smoke exposure. These experiments will quantify acetaldehyde-protein binding and dysfunction in the cilia of tissues exposed to acetaldehyde vapor, cigarette smoke and ethanol both in vitro and in vivo.

申请人摘要：酗酒者会增加肺部疾病的发生率 部分归因于肺宿主防御功能改变的疾病 与酒精中毒和酗酒者吸烟的强烈倾向有关 重重。 主要气道防御功能在这两种情况下均受损 饮酒和吸烟是粘液纤毛清除 系统。 两者共有的一种可能的粘液纤毛损伤机制 饮酒和吸烟是乙醛暴露，因为乙醛 是在肝脏和局部乙醇代谢过程中产生的 存在于气道中，并且在气相中也有大量存在 香烟烟雾。 这很重要，因为乙醛是一种高度 反应分子已被认为是一种重要的毒素 与其共价结合反应性的能力相关的生物系统 蛋白质残留物。 初步实验已经证明了影响 乙醛对支气管上皮细胞纤毛的影响。 这些研究 确定乙醛对纤毛气道有直接毒性 上皮细胞导致纤毛减慢或麻痹，抑制纤毛动力蛋白 ATP 酶活性，并与对运动至关重要的纤毛蛋白结合 特别是动力蛋白和微管蛋白。 因此，假设： 乙醛通过与关键纤毛结合而损害气道纤毛功能 蛋白质，包括动力蛋白和微管蛋白，在遇到的浓度 饮酒和吸烟期间。 为了检验这个假设 提出以下具体目标： 1) 评估 乙醛与轴丝动力蛋白和微管蛋白结合并损害 ATP 酶 动力蛋白的活性。 这些实验将测量化学计量和 乙醛的竞争性结合和纯化的功能损伤 纤毛动力蛋白和微管蛋白。 2) 阐明其机制 乙醛结合损害轴丝动力蛋白与 微管蛋白和微管。 这些实验将检验乙醛的 对动力蛋白增强微管聚合能力的影响 在无细胞系统中易位微管。 3）评估重要性 乙醛暴露是导致纤毛功能障碍的原因 酒精和烟雾暴露。 这些实验将量化 乙醛-蛋白质结合和组织纤毛功能障碍 体外暴露于乙醛蒸气、香烟烟雾和乙醇 和体内。

项目成果

Desensitization of PKA-stimulated ciliary beat frequency in an ethanol-fed rat model of cigarette smoke exposure.

• DOI: 10.1097/01.alc.0000130805.75641.f4
• 发表时间: 2004-07
• 期刊: Alcoholism, clinical and experimental research
• 作者: T. Wyatt;M. Gentry-Nielsen;Jacqueline A. Pavlik;J. Sisson

Effectiveness and safety of the awakening and breathing coordination, delirium monitoring/management, and early exercise/mobility bundle.

• DOI: 10.1097/ccm.0000000000000129
• 发表时间: 2014-05
• 期刊: Critical care medicine
• 影响因子: 8.8
• 作者: Balas MC;Vasilevskis EE;Olsen KM;Schmid KK;Shostrom V;Cohen MZ;Peitz G;Gannon DE;Sisson J;Sullivan J;Stothert JC;Lazure J;Nuss SL;Jawa RS;Freihaut F;Ely EW;Burke WJ
• 通讯作者: Burke WJ

GEF1 is a ciliary Sec7 GEF of Tetrahymena thermophila.

GEF1 是嗜热四膜虫的纤毛 Sec7 GEF。

• DOI: 10.1002/cm.20348
• 发表时间: 2009
• 期刊: Cell motility and the cytoskeleton
• 作者: Bell,AaronJ;Guerra,Charles;Phung,Vincent;Nair,Saraswathy;Seetharam,Raviraja;Satir,Peter
• 通讯作者: Satir,Peter

Use of a novel cell adhesion method and digital measurement to show stimulus-dependent variation in somatic and oral ciliary beat frequency in Paramecium.

• DOI: 10.1111/jeu.12153
• 发表时间: 2015-01
• 期刊: The Journal of eukaryotic microbiology
• 作者: Bell WE;Hallworth R;Wyatt TA;Sisson JH
• 通讯作者: Sisson JH

Alcohol potentiates RSV-mediated injury to ciliated airway epithelium.

酒精会增强 RSV 介导的纤毛气道上皮损伤。

• DOI: 10.1016/j.alcohol.2018.07.010
• 发表时间: 2019
• 期刊: Alcohol (Fayetteville, N.Y.)
• 作者: Wyatt,ToddA;Bailey,KristinaL;Simet,SamanthaM;Warren,KristiJ;Sweeter,JeneaM;DeVasure,JaneM;Pavlik,JaquelineA;Sisson,JosephH
• 通讯作者: Sisson,JosephH