Airway Injury Caused by MAA Adducts

MAA 加合物引起的气道损伤

基本信息

批准号：
7878548
负责人：
Todd A Wyatt
金额：
$ 41.45万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-15 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7878548
关键词：
Acetaldehyde Address Agonist Alcohol consumption Alcoholic beverage heavy drinker Alcohols Aldehydes Animals Asthma Bacterial Infections Binding Breathing Cell Line Cells Chronic Chronic Bronchitis Chronic lung disease Cigarette Cilia Clinical Consumption Cyclic Nucleotides Disease Epithelial Cells Etiology Exposure to Fibrosis Functional disorder Health Hybrids Immune Impairment In Vitro Infection Inflammatory Injury Lung Lung Inflammation Lung Lavage Fluid Lung diseases Malondialdehyde Mediating Membrane Modality Modeling Motor Mucociliary Clearance Mus Nitric Oxide Pathologic Phosphorylation Phosphotransferases Play Production Protein Binding Proteins Public Health Pulmonary Emphysema Receptor Activation Reporting Research Role Signal Transduction Pathway Small Interfering RNA Smoke Smoker Smoking Stimulus Testing Time Toxin adduct airway epithelium alcohol effect alcohol exposure base cell motility cigarette smoking cigarette smoking disorder prevention feeding hepatic necrosis in vivo inhibitor/antagonist injured injured airway innovation interest lung injury mouse model particle pathogen problem drinker protein activation protein kinase C epsilon receptor binding research study response restoration scavenger receptor therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Our overall interest is chronic inflammatory lung disease mechanisms in the context of combined alcohol use and cigarette smoking. Some studies report that up to 30% of smokers are heavy alcohol users. The airways of smokers who drink alcohol are more susceptible to bacterial infection and colonization, suggesting a compromise in the protective mucociliary apparatus. We hypothesize that prolonged exposure to the unique combination of cigarette smoking and ethanol consumption results in the impairment of the mucociliary transport apparatus. Large concentrations of malondialdehyde and acetaldehyde are found in the lungs of smoking alcoholics. Accumulation of lung aldehydes results in formation of hybrid aldehyde adducted proteins that produce pro-inflammatory effects parallel to liver necrosis and fibrosis. One such airway protein adduct is the malondialdehyde-acetaldehyde (MAA) adduct. The major mechanism of protein adduct binding to cells is via membrane scavenger receptors. We will explore the relationship between MAA adducts, alcohol consumption, and cigarette smoking with the following specific aims: 1) Determine if co-exposure to the combination of cigarette smoke and alcohol results in unique alterations to the mucociliary transport apparatus. 2) Determine if co-exposure to smoke and alcohol results in the formation of MAA adducts. 3) Identify the scavenger receptor that binds MAA-adducted protein to airway epithelium. 4) Determine the mechanism of action for MAA adduct-mediated cilia slowing. With these aims, we will establish an association between alcohol consumption, cigarette smoking and cilia dysfunction as mediated by MAA adduct formation. While the etiology of chronic inflammatory lung diseases is largely unknown and likely multi-faceted, the study of MAA adduct formation is an innovative approach to the pathologic interaction between cigarette smoke and alcohol. PUBLIC HEALTH SIGNIFICANCE: This study greatly impacts public health. It has long been clinically known that chronic lung disease and lung infections are much more severe in alcoholics. Nearly all alcoholics smoke cigarettes. Our studies seek to define the mechanisms that injure proper lung clearance and health under conditions of combined smoke and alcohol consumption. Understanding the mechanisms of such injury will define the subsequent treatment modalities to restoring normative lung mucociliary clearance function and directly address disease prevention in the approximately 20 million US alcoholics.

描述（由申请人提供）：我们的总体兴趣是在饮酒和吸烟的情况下，慢性炎症性肺部疾病机制。一些研究报告说，多达30％的吸烟者是大量酒精使用者。饮酒的吸烟者的气道更容易受到细菌感染和定殖的影响，这表明在保护性粘膜固定装置中会受到妥协。我们假设长期暴露于吸烟和乙醇消耗的独特组合会导致粘膜转运设备受损。在吸烟酗酒者的肺中发现了大量的丙二醛和乙醛。肺醛的积累会导致形成杂交醛加成的蛋白质，从而产生与肝坏死和纤维化平行的促炎作用。这样的气道蛋白加合物之一是丙二醛 - 乙醛（MAA）加合物。蛋白质加合物与细胞结合的主要机制是通过膜清道夫受体。我们将探索MAA加合物，饮酒和吸烟与以下特定目的之间的关系：1）确定对香烟烟雾和酒精的共同暴露是否会导致粘膜纤毛运输设备的独特变化。 2）确定烟气和酒精的共曝光是否导致MAA加合物的形成。 3）确定将MAA添加蛋白与气道上皮结合的清道夫受体。 4）确定MAA加合物介导的纤毛减慢的作用机理。通过这些目标，我们将建立通过MAA加合物形成介导的饮酒，吸烟和纤毛功能障碍之间的关联。虽然慢性炎性肺部疾病的病因在很大程度上是未知的，并且可能是多方面的，但MAA加合物形成的研究是一种创新的方法，是香烟烟与酒精之间病理相互作用的一种创新方法。公共卫生意义：这项研究极大地影响了公共卫生。长期以来，临床上已经知道慢性肺部疾病和肺部感染在酒精中毒中要严重得多。几乎所有酒精饮料都抽烟。我们的研究旨在定义在烟雾和饮酒综合条件下损害适当的肺部清除和健康的机制。了解这种损伤的机制将定义随后的治疗方式来恢复规范性肺部粘膜钙毛的清除功能，并直接解决约2000万美国酒精中毒的疾病预防。