The Exposome and Lung Bacterial Infection: Role of Liver and Gut-derived Extracellular Vesicles

暴露体和肺部细菌感染：肝脏和肠源性细胞外囊泡的作用

• 批准号: 10526256
• 负责人: Todd A Wyatt
• 金额: $ 24.18万
• 依托单位: UNIVERSITY OF NEBRASKA 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: 2023-02-28 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10526256
• 关键词: Acute; Address; Alcohol consumption; Alcohols; Aldehydes; American; Animal Model; Bacteria; Bacterial Infections; Bacterial Pneumonia; Binding; Blood; Cause of Death; Cell model; Cells; Characteristics; Chronic; Chronic Obstructive Pulmonary Disease; Cigarette; Cilia; Clinical; Communication; Complex; Coupled; Defensins; Development; Diagnosis; Disease; Distal; Environmental Exposure; Enzymes; Epithelial Cells; Ethanol Metabolism; Exposure to; Functional disorder; Future; General Population; Host Defense; Human; Impairment; Incidence; Individual; Infection; Injury; International; Investigation; Knowledge; Laboratories; Life; Liver; Lung; Lung diseases; Lung infections; Macrophage; Malnutrition; Mediating; Membrane; Metabolic; Modality; Modeling; Modification; Morbidity - disease rate; Mucociliary Clearance; Mus; Nebraska; Nutrient; Nutritional; Organ; Organoids; Pathogenesis; Pathology; Pharmacy facility; Play; Pneumococcal Pneumonia; Pneumonia; Predisposition; Preventive care; Pulmonary Surfactant-Associated Protein D; Research; Research Personnel; Risk; Role; Sampling; Scientist; Severities; Smoke; Smoker; Source; Stream; Streptococcus pneumoniae; Sum; Testing; Time; Tissues; Vesicle; Zinc; Zinc deficiency; alcohol effect; alcohol exposure; alcohol misuse; alcohol research; alcohol use disorder; antimicrobial; biobank; bronchial epithelium; career; cigarette smoke; cigarette smoking; cilium motility; clinical care; comorbidity; empowerment; experience; exposure to cigarette smoke; extracellular vesicles; gut dysbiosis; gut microbiome; gut-liver axis; gut-lung axis; interest; liver injury; lung injury; lung repair; microbicide; microbiota; mortality; mouse model; novel; nutrition; organ injury; professor; response; skills; smoke inhalation; surfactant; targeted treatment; tissue injury; tobacco exposure

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 to optimize clinical care. Disease is impacted by the sum of all environmental exposures during one’s life. Collectively referred to as the exposome, little alcohol-mediated lung injury has taken into consideration such real-world complexity. In this 5-year project, we will investigate the alcohol exposome in lung bacterial infections. Compared to the general public, 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. Likewise, nutritional deficiencies play an important role in disease pathogenesis. Our knowledge about how such exposome characteristics impact alcohol-mediated lung injury 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 pulmonologist whose expertise is on characterizing primary human lung clinical samples, experienced alcohol liver injury researcher with extracellular vesicle expertise, a senior professor of pharmacy recognized internationally as a zinc expert, and a junior investigator who is already an expert in alcohol-mediated gut dysbiosis 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 a complex exposome model of alcohol, cigarette smoking, and zinc deficiency. We will specifically identify in these groups any changes in cilia beat controlling clearance and the role of reactive aldehydes generated by liver- and gut-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，酒精滥用与肺炎的增加有关。虽然酒精的作用 细菌性肺炎的易感性和严重性仍有待充分了解，因此，必须确定在 风险条件和那些谁滥用酒精的独特需求，并立即这样做，以优化临床 在乎疾病受到一生中所有环境暴露的总和的影响。统称 酒精介导的肺损伤是一个麻烦的问题，很少有人考虑到这种现实世界的复杂性。在 这个5年的项目，我们将研究酒精代谢酶在肺部细菌感染中的作用。相比 一般公众，酒精使用障碍（AUD）患者的特点是大量吸烟 导致预先存在的肺部疾病，如慢性阻塞性肺疾病（COPD），一种主要的并发症， 肺炎的发病率。同样，营养缺乏在疾病发病机制中起重要作用。我们 关于这些麻烦的特征如何影响酒精介导的肺损伤的知识是有限的。然而，在这方面， 我们以前的肺部酒精研究结果已经证明AUD与纤毛有关 功能障碍我们的研究结果还表明，AUD导致表面活性剂抗微生物作用降低。 表面活性剂蛋白D已被证明特异性地结合并聚集细菌，以获得最佳的生物活性。 杀菌作用。我们推测，在粘膜纤毛清除水平上改变先天性肺防御， 抗微生物表面活性剂会对细菌性肺炎的易感性和发病机制产生负面影响， 特别是在伤害的方式与AUD的个人。我们的调查人员组成的团队包括一个VA研究 职业科学家，在酒精对肺损伤和修复的影响方面拥有26年的经验，肺病学家 其专长是表征原发性人肺临床样本，经历过酒精肝损伤， 具有细胞外囊泡专业知识的研究员，国际公认的药学高级教授， 锌专家，和一个初级研究员谁已经是一个专家，酒精介导的肠道生态失调和细菌 感染.我们在酒精损伤小鼠模型方面的专业知识与我们现有的生物库相结合， 人肺细胞和组织，我们建议通过鉴定S. 酒精、吸烟和锌的复杂干扰模型引起的肺炎感染反应 缺陷我们将特别确定在这些组中纤毛搏动控制清除的任何变化， 肝和肠源性细胞外囊泡产生的活性醛的作用。这些研究将 首次在与AUD相关的动物和细胞模型中进行。确定风险的形式还将 使临床医生能够在酒精滥用的情况下做出知情的预防性护理决定。