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

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- 滥用酒精者的风险状况和独特需求，并立即这样做，以优化临床 关心。疾病受一个人一生中所有环境暴露的总和的影响。统称为 正如所揭示的那样，很少有酒精介导的肺损伤考虑到了这种现实世界的复杂性。在……里面 在这个为期5年的项目中，我们将调查酒精暴露在肺部细菌感染中的情况。与之相比 对于普通大众来说，那些有酒精使用障碍(AUD)的人的特征是大量吸烟 导致先前存在的肺部疾病，如慢性阻塞性肺疾病(COPD)，一个主要的共同 肺炎的发病率。同样，营养缺乏在疾病的发病机制中也起着重要作用。我们的 关于这种暴露特征如何影响酒精介导的肺损伤的知识有限。然而， 我们先前的肺酒精研究结果已经证明，AUD与纤毛有关。 功能障碍。我们的结果还表明，AUD会降低表面活性剂的抗微生物作用。 表面活性蛋白D已被证明可以与细菌特异性结合并聚集在一起，以获得最佳的 杀微生物剂。我们假设，在粘液纤毛清除水平上改变了先天肺防御系统 抗菌表面活性物质将对细菌性肺炎的易感性和发病机制产生负面影响， 患有澳元缺乏症的人，尤其是处于危险中的人。我们组建的调查团队包括一家退伍军人研究公司 职业科学家，在酒精对肺损伤和修复的影响方面有26年的经验，是一名肺科医生 他的专长是鉴定原发人类肺部临床样本，经历过酒精性肝损伤 具有细胞外囊泡专业知识的研究员，国际公认的资深药学教授 锌专家，一名初级研究员，已经是酒精介导的肠道菌群失调和细菌方面的专家 感染。我们在酒精损伤小鼠模型方面的成熟专业知识与我们现有的生物库 对于人类肺细胞和组织，我们建议通过识别S。 由酒精、吸烟和锌的复杂暴露模型引起的肺炎感染反应 缺乏症。我们将在这些组中具体确定纤毛节拍控制清除和 肝脏和肠道来源的胞外小泡产生的反应性醛的作用。这样的研究将是 首次在与AUD相关的动物和细胞模型中进行了实验。定义风险的形式也将 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。

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.