Reactive aldehydes and alcohol misuse in lung infections

肺部感染中的活性醛和酒精滥用

• 批准号: 10581148
• 负责人: Todd A Wyatt
• 金额: --
• 依托单位: OMAHA VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10581148
• 关键词: 3-Dimensional; Acetaldehyde; Address; Adhesions; Alcohol abuse; Alcohol consumption; Alcohol dehydrogenase; Alcohols; Aldehydes; Animal Feed; Animal Model; Bacteria; Bacterial Infections; Bacterial Model; Bacterial Pneumonia; Binding; Cell model; Cells; Cessation of life; Characteristics; Chronic Obstructive Pulmonary Disease; Cigarette Smoker; Cilia; Clinical; Collectins; Cytochromes; Defensins; Disease; Enzymes; Epithelial Cells; Epithelium; Functional disorder; Hepatocyte; Human; Impairment; In Vitro; Individual; Infection; Injury; Innate Immune System; Intervention; Knowledge; Lead; Literature; Liver; Lung; Lung diseases; Lung infections; Macrophage; Malondialdehyde; Mediating; Modality; Modeling; Morbidity - disease rate; Mucociliary Clearance; Mus; Organoids; Pathogenesis; Phagocytosis; Pneumonia; Predisposing Factor; Predisposition; Preventive care; Production; Proteins; Pulmonary Surfactant-Associated Protein D; Research; Research Personnel; Risk; Role; Sampling; Scientist; Severities; Smoke; Smoker; Smoking; Source; Streptococcus pneumoniae; Structure; Testing; Time; Tissues; active duty; adduct; airway epithelium; alcohol exposure; alcohol misuse; alcohol research; alcohol use disorder; antimicrobial; biobank; career; cigarette smoke; cigarette smoking; clinical care; comorbidity; cost; empowerment; experience; extracellular vesicles; in vivo; in vivo Model; inflammatory lung disease; liver injury; lung development; lung injury; lung pathogen; lung repair; microbicide; military veteran; mortality; mouse model; pulmonary function; response; surfactant; translational impact

Pneumonia is one of the leading causes of morbidity and mortality, particularly in older individuals. Importantly, alcohol misuse has been associated with increased pneumonia for over 200 years. While the role of alcohol in bacterial pneumonia susceptibility and severity remains to be fully understood, it is essential to define the at- risk conditions and unique needs of those who misuse alcohol and to do so immediately in order to optimize clinical care. Common in both active-duty and the veterans’ population, those with alcohol use disorders (AUD) can be characterized by heavy cigarette smoking leading to pre-existing lung diseases such as chronic obstructive pulmonary disease (COPD), a major co-morbidity for pneumonia. Our knowledge about how such characteristics impact this pathogenesis is limited. However, results from our previous lung alcohol research have already demonstrated that AUD are associated with cilia dysfunction. Our results also demonstrate that AUD results in decreased surfactant anti-microbial action. Surfactant protein D has been documented to specifically bind to and aggregate bacteria for optimal microbicidal action. We hypothesize that altered innate lung defense at the level of mucociliary clearance and anti-microbial surfactants will negatively impact susceptibility and pathogenesis of bacterial pneumonia, placing individuals with AUD particularly in harm’s way. Our assembled team of investigators include a VA Research Career Scientist with 26 years’ experience in the impact of alcohol on lung injury and repair, a VA pulmonologist whose expertise is on characterizing primary human lung clinical samples, experienced alcohol liver injury researchers, and a junior investigator who is already an expert in working with alcohol and bacterial infections. Our established expertise in mouse models of alcohol injury combined with our existing biobank of human lung cells and tissues, we propose to address our hypothesis by identifying any differences in S. pneumoniae infection responses due to alcohol and/or cigarette smoking. We will specifically identify in these groups any changes in cilia beat controlling clearance, surfactant protein D structure/function, and the role of reactive aldehydes generated by liver-derived extracellular vesicles. Such studies will be performed for the first time in animal and cell models relevant to AUD. Defining the modalities of risk will also empower clinicians to make informed preventive care decisions in the context of alcohol misuse.

肺炎是发病率和死亡率的主要原因之一，特别是在老年人中。重要的是 200多年来，酗酒一直与肺炎的增加有关。而酒精在人体内的作用 细菌性肺炎的易感性和严重性仍有待充分了解，有必要确定- 滥用酒精的人的风险状况和独特需求，并立即这样做，以便优化 临床护理。在现役军人和退伍军人中都很常见，即那些有酒精使用障碍(AUD)的人 可能以大量吸烟导致先前存在的肺部疾病为特征，如慢性 阻塞性肺疾病(COPD)，肺炎的主要并存疾病。我们对这一点的了解 特征对本病的影响有限。然而，我们之前的肺酒精研究结果 已经证明AUD与纤毛功能障碍有关。我们的结果还表明， AUD导致表面活性物质的抗微生物作用减弱。表面活性蛋白D已被记载为 专门结合和聚集细菌，以达到最佳的杀菌作用。我们假设是先天改变的 肺防御在粘液纤毛清除和抗微生物表面活性物质的水平上会产生负面影响 细菌性肺炎的易感性和发病机制，使患有AUD的人处于特别危险的境地 道路。我们组建的调查团队包括一名退伍军人研究职业科学家，拥有26年的 酒精对肺损伤和修复的影响，退伍军人管理局的肺科医生，他的专长是 原始人类肺临床样本，经验丰富的酒精性肝损伤研究人员，以及初级研究员 世卫组织已经是酒精和细菌感染方面的专家。我们在鼠标方面的成熟专业知识 酒精损伤模型结合我们现有的人肺细胞和组织生物库，我们建议 通过确定酒精引起的肺炎链球菌感染反应的任何差异来验证我们的假设 和/或吸烟。我们将在这些组中明确确定纤毛节拍控制的任何变化 清除，表面活性蛋白D的结构/功能，以及肝脏产生的反应性醛的作用 胞外小泡。这类研究将首次在动物和细胞模型中进行， 澳元。定义风险的模式还将使临床医生能够在以下方面做出知情的预防性护理决定 酒精滥用的背景。