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.

肺炎是发病和死亡的主要原因之一，尤其是老年人。 200 多年来，酒精滥用与肺炎增加有关。 细菌性肺炎的易感性和严重程度仍有待充分了解，有必要定义 滥用酒精者的风险状况和独特需求，并立即这样做，以优化 临床护理在现役军人和退伍军人中都很常见，患有酒精使用障碍（AUD）的人。 其特点是大量吸烟导致先前存在的肺部疾病，例如慢性 阻塞性肺病（COPD）是肺炎的一种主要并发症，我们对此的了解。 然而，我们之前的肺酒精研究结果表明，这些特征对这种发病机制的影响是有限的。 已经证明 AUD 与纤毛功能障碍有关。我们的结果也证明了这一点。 AUD 会导致表面活性剂蛋白 D 的抗菌作用降低。 专门用于结合和聚集细菌以获得最佳的杀菌作用。 粘膜纤毛清除水平的肺防御和抗菌表面活性剂将对肺防御产生负面影响 细菌性肺炎的易感性和发病机制，使 AUD 患者特别容易受到伤害 我们组建的研究团队包括一位在 VA 研究领域拥有 26 年经验的职业科学家。 酒精对肺损伤和修复的影响，退伍军人管理局肺科医生，其专业知识是表征 主要人类肺部临床样本、经验丰富的肝酒精损伤研究人员和初级研究员 他已经是处理酒精和细菌感染方面的专家，我们在小鼠方面拥有丰富的专业知识。 酒精损伤模型结合我们现有的人类肺细胞和组织生物库，我们建议 通过识别酒精引起的肺炎链球菌感染反应的差异来验证我们的假设 我们将特别确定这些群体中纤毛跳动控制的任何变化。 清除率、表面活性蛋白 D 结构/功能以及肝源性产生的活性醛的作用 此类研究将首次在与细胞外囊泡相关的动物和细胞模型中进行。 AUD. 定义风险模式还将使人们能够做出明智的预防性护理决策。 滥用酒精的背景。