Airway Injury Caused by MAA Adducts

描述（由申请人提供）：我们的总体兴趣是在联合饮酒和吸烟的背景下慢性炎症性肺病的机制。一些研究报告说，多达30%的吸烟者是重度酒精使用者。饮酒的吸烟者的气道更容易受到细菌感染和定植，这表明保护性粘膜纤毛装置的妥协。我们推测，长期暴露于吸烟和酒精消费的独特组合导致粘膜纤毛运输装置受损。在吸烟酗酒者的肺中发现了大量的丙二醛和乙醛。肺醛的积累导致形成杂合醛加合蛋白，其产生与肝坏死和纤维化平行的促炎作用。一种这样的气道蛋白加合物是丙二醛-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、饮酒和吸烟之间的关系，具体目标如下：1）确定共同暴露于香烟烟雾和酒精的组合是否导致粘膜纤毛运输装置的独特改变。2)确定是否共同暴露于烟雾和酒精导致MAA加合物的形成。3)识别结合MAA加合蛋白与气道上皮的清道夫受体。4)确定MAA内收物介导的纤毛减慢的作用机制。有了这些目标，我们将建立一个关联饮酒，吸烟和纤毛功能障碍介导的MAA加合物的形成。虽然慢性炎性肺病的病因在很大程度上是未知的，可能是多方面的，MAA加合物形成的研究是香烟烟雾和酒精之间的病理相互作用的创新方法。公共卫生意义：这项研究极大地影响了公共卫生。长期以来，临床上都知道慢性肺部疾病和肺部感染在酗酒者中更为严重。几乎所有的酗酒者都吸烟。我们的研究试图确定在吸烟和饮酒的条件下损害适当的肺清除和健康的机制。了解这种损伤的机制将确定随后的治疗方式，以恢复正常的肺粘膜纤毛清除功能，并直接解决约2000万美国酗酒者的疾病预防问题。

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.