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

基本信息

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
项目类别：
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

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

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项目摘要

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，尤其是在老年人中。重要的是，滥用酒精与肺炎增加了200多年。而酒精的作用细菌性肺炎的敏感性和严重程度尚待充分理解，至关重要的是那些错过酒精并立即这样做以优化临床的人的风险条件和独特的需求关心。疾病受到一生中所有环境暴露的总和的影响。集体提及作为揭示，几乎没有酒精介导的肺损伤考虑到这种现实世界中的复杂性。在这个为期5年的项目，我们将研究肺细菌感染中的酒精外博。与普通大众，那些患有酒精饮酒障碍的人（AUD）可以以大量香烟吸烟为特征导致先前存在的肺部疾病，例如慢性阻塞性肺疾病（COPD），这是主要共同的肺炎的发病率。同样，营养缺乏在疾病发病机理中起重要作用。我们的关于这种杂菌体特征如何影响酒精介导的肺损伤的知识受到限制。然而，我们以前的肺酒精研究的结果已经证明AUD与纤毛有关功能障碍。我们的结果还表明，AUD导致生存抗菌作用改善。表面活性剂蛋白D已被记录在特异性结合和聚集细菌以获得最佳微生物作用。我们假设在粘膜清除水平上改变了先天肺防御和抗微生物表面活性剂将对细菌肺炎的敏感性和发病机理产生负面影响，并放置具有AUD的人特别受到伤害。我们组建的调查人员团队包括VA研究职业科学家拥有26年的肺科医生，在酒精对肺损伤和维修的影响方面拥有26年的经验其专业知识是特征原发性人类肺临床样本，经历了酒精肝损伤细胞外囊泡专业知识的研究人员，药学高级教授在国际上被认为是锌专家，以及已经是酒精介导的肠癌和细菌专家的初级研究员感染。我们在鼠标损伤的老鼠模型中既定的专业知识，结合了我们现有的生物库人类肺细胞和组织，我们建议通过确定S.中的任何差异来解决我们的假设。肺炎感染反应是由于复杂的酒精，吸烟和锌的复杂释放模型而引起的不足。我们将在这些小组中明确识别纤毛控制的任何变化控制清除率和由肝和肠细胞外蔬菜产生的反应性醛的作用。这样的研究将是在与AUD相关的动物和细胞模型中首次进行。定义风险方式也将授权临床医生在滥用酒精的情况下做出明智的预防性护理决定。