Clinical Resource for Lung and Alcohol Investigations

描述（由申请人提供）：在美国，肺炎是酒精使用障碍（AUDs）患者中常见且严重的疾病。尽管在动物模型和小规模人体研究中有许多有趣的观察结果，但没有一项进展到旨在降低AUDs患者肺炎发病率的临床试验。为了促进该领域的创新，科罗拉多大学丹佛分校（UCD）的研究人员正在寻求支持，领导一个由埃默里大学（EU）、路易斯安那州立大学（LSU）、洛约拉大学（LUMC）和内布拉斯加州大学（UNMC）等4个主要机构组成的酒精相关肺炎研究联盟，研究AUDs对人类受试者肺炎易感性的影响。我们将利用这一资源来验证酒精相关的肺氧化应激、细胞因子环境和内源性蛋白质的改变，通过对肺泡巨噬细胞和支气管气道上皮细胞功能的影响，以及对呼吸道微生物群的影响，导致肺炎易感性增加的假设。在R24的支持下，我们将扩大UCD的现有资源，从EU和LSU的aud受试者和匹配的对照组以及LUMC和UCD的烧伤患者中获取额外的样本和数据。明尼苏达大学的生物保存专家将在适当的样品处理和储存方面提供帮助，以确保高质量的实验结果。具体目标将包括确定AUDs通过影响肺泡巨噬细胞肠细胞吞噬、细胞凋亡和成熟增加肺炎易感性的机制及其与锌缺乏和肺氧化应激的关系；(2)支气管气道上皮细胞功能，包括toll样受体-2的表达、纤毛功能以及对AUDs和吸烟环境下形成的蛋白质加合物的反应；(3)呼吸道微生物生态及其与肺泡腔抗菌蛋白组成/功能改变以及肺/全身细胞因子环境改变的关系。

DESCRIPTION (provided by applicant): Pneumonia is a common and serious medical condition among individuals with alcohol use disorders (AUDs) in the US. Despite numerous intriguing observations in animal models and small scale human investigations, none have progressed forward into clinical trials aimed at decreasing the incidence of pneumonia in those with AUDs. To promote innovation in the field, investigators at the University of Colorado Denver (UCD) are seeking support to lead a consortium comprised of 4 premier sites in alcohol- related pneumonia research, including Emory University (EU), Louisiana State University (LSU), Loyola University (LUMC), and the University of Nebraska (UNMC) to investigate the effect of AUDs on susceptibility for pneumonia in human subjects. We will utilize this resource to test the hypothesis that alcohol-related alterations on pulmonary oxidative stress, the cytokine milieu, and endogenous proteins lead to an increased susceptibility to pneumonia through their influence on alveolar macrophage and bronchial airway epithelial cell function, and their influence on the respiratory tract microbiome. With this R24 support, we will expand an established resource at UCD by obtaining additional samples and data from subjects with AUDs and matched controls from EU and LSU, and from burned patients at LUMC and UCD. Support from biopreservation experts at the University of Minnesota will provide assistance in appropriate sample processing and storage to ensure quality experimental results. Specific aims will include determining the mechanisms whereby AUDs increase the predisposition to pneumonia via effects on (1)alveolar macrophage enterocytosis, apoptosis, and maturation and their relationship to zinc deficiency and pulmonary oxidative stress; (2)bronchial airway epithelial cell function, including expression of toll-like receptor-2, ciliary function, and response to protein adducts formed in the setting of AUDs and smoking; (3)respiratory tract microbial ecology, and its relationship to alterations in antimicrobial protein composition/function in the alveolar space, and alterations in pulmonary/systemic cytokine milieu in the presence and absence of burn injury. RELEVANCE: Alcohol-related pneumonias are a significant health care burden to the US. Research in this field has been hampered previously by the lack of an established infrastructure to conduct translational investigations in individuals with alcohol use disorders. Creating a consortium to share clinical samples and data relevant to the study of alcohol-associated pneumonias with committed investigators will promote discovery in this field.