Malondialdehyde-acetaldehyde adducts and lung injury

目的与临床关系：我们的长期目标是识别酒精所致的组织损伤 在酒精使用障碍(AUD)患者中观察到的机制，以便更好地早期生物标志物 可以发展损伤，从而改进方法，将病原体的敏感性降至最低，并防止 肺炎的高昂代价。 研究设计与方法：酗酒导致肺炎易感性增加 已经有200多年的历史了。NIAAA的出版物称，有酒精使用障碍的住院患者 急性尿毒症(AUDS)因肺炎死亡的风险是普通人的3倍。酒精调节先天的和适应性的 肺部的免疫系统导致易感性增加，感染的解决率降低。20美元 多年来，我们的研究小组在研究酒精对天生的慢性影响方面一直是公认的领导者 由粘液纤毛运输器提供的免疫力。因为大多数(90%)患有 AUDS吸烟，我们选择采取与公共健康相关的方法来研究 香烟和酒精的联合肺损伤效应。在我们之前的融资周期中，我们发现 肺是形成稳定的丙二醛-乙醛蛋白的独特环境。 加合物(MAA加合物)，但仅在吸烟和酒精联合暴露的情况下。这些 MAA加合物导致呼吸道上皮细胞纤毛减慢，并损害肺内天然病原体的清除。 我们已发表的和初步的数据表明，表面活性蛋白D(SPD)是一种主要的肺蛋白， 在吸烟和酒精联合暴露期间，肺醛浓度升高时会被引用。 使用来自NIAAA支持的科罗拉多州肺酒精研究联盟的人体样本， 我们发现MAA加合物只在个体的肺灌洗液、巨噬细胞和肺液中检测到。 也吸烟的AUDS患者。我们观察到，AUD吸烟者肺粘膜SIgA和 MAA加合物治疗呼吸道上皮可阻断SIgA粘膜分泌物的跨细胞处理。 由于这些重要而新颖的观察，我们现在建议扩大我们对 MAA加合物对肺巨噬细胞、粘膜SIgA和SPD的致病作用。我们的总体假设是 MAA加合物在同时饮酒和吸烟的人的肺中以独特的形式存在， 导致先天肺防御系统的改变。我们将通过三个目标来研究这一假设：目标1：MAA 加合物肺SPD(MAA-SPD)通过清道夫受体A与肺巨噬细胞结合 巨噬细胞功能；目的2：MAA-SPD通过改变上皮细胞来阻止SIgA在肺粘膜的分泌 目标3：SPD的MAA加成降低了其抗微生物作用。

Objective & Clinical Relationship: Our long-term goal is to identify the alcohol-mediated tissue injury mechanisms observed in individuals with alcohol-use disorders (AUDs) so that better early biomarkers of injury can be developed leading to enhanced approaches to minimize pathogen susceptibility and prevent the high costs of pneumonia. Research Design & Methodology: Alcohol abuse causing increased susceptibility to pneumonia has been known for over 200 years. NIAAA publications state that hospitalized individuals with alcohol use disorders (AUDs) have a 3-fold risk of mortality from pneumonia. Alcohol modulates both the innate and adaptive immune systems of the lung resulting in increased susceptibility and decreased resolution of infection. For 20 years, our research group has been a recognized leader in studying the chronic effects of alcohol on the innate immunity provided by the mucociliary transport apparatus. Because the majority (>90%) individuals with AUDs smoke cigarettes, we have chosen to take the public health relevant approach of studying the combination lung injury effects of both cigarettes and alcohol. In our previous funding cycle, we identified that the lungs represent a unique environment for the formation of stable malondialdehyde-acetaldehyde protein adducts (MAA adducts), but only under conditions of combined cigarette smoke and alcohol exposure. These MAA adducts cause airway epithelial cell cilia slowing and impair the innate pathogen clearance from the lung. Our published and preliminary data demonstrate that surfactant protein D (SPD) is a major lung protein that gets adducted when lung aldehyde concentrations are elevated during combined smoke and alcohol exposure. Using human samples derived from the NIAAA-supported Colorado Pulmonary Alcohol Research Consortium, we have found that MAA adducts are detected in the lung lavage macrophages and fluid only in individuals with AUDs who also smoke. We have observed that the AUD smokers have decreased lung mucosal sIgA and that MAA adduct treatment of airway epithelium blocks transcytotic processing of sIgA mucosal secretion. Because of these important and novel observations, we now propose to extend our research on the pathogenesis of the MAA adduct to lung macrophages, mucosal sIgA, and SPD. Our overall hypothesis is that MAA adducts uniquely form in the lungs of individuals who consume both alcohol and smoke cigarettes, leading to alterations in innate lung defense. We will investigate this hypothesis through 3 aims: Aim 1: MAA adducted lung SPD (MAA-SPD) binds to lung macrophages via scavenger receptor A leading to alterations in macrophage function; Aim 2: MAA-SPD prevents sIgA mucosal secretion in lung by altering epithelial cell processing of dimerized IgA; and Aim 3: MAA adduction of SPD decreases its anti-microbial action.