The role of the lung microbiome in oxygen-induced lung injury

肺微生物组在氧诱导性肺损伤中的作用

• 批准号: 9754347
• 负责人: Robert Pickett Dickson
• 金额: $ 42.26万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9754347
• 关键词: Acute; Adult Respiratory Distress Syndrome; Alveolar; Animals; Antibiotics; Bacteria; Biological Assay; Bleomycin; Clinical; Data Science; Development; Disease; Ecology; Ecosystem; Environment; Experimental Models; Feedback; Germ-Free; Gnotobiotic; Growth; Heterogeneity; Human; Hyperoxia; Immune response; Inflammation; Inhalation; Injury; Lung; Lung diseases; Mediating; Mediator of activation protein; Modeling; Molecular; Mus; Nature; Observational Study; Outcome; Oxidative Stress; Oxygen; Oxygen Therapy Care; Pathogenesis; Pathway interactions; Prevention; Prevention therapy; Publishing; Research; Respiratory System; Role; Severities; Sterility; Translational Research; dysbiosis; host microbiome; host microbiota; human data; in vivo; injured; lung injury; lung microbiome; lung microbiota; machine learning algorithm; member; microbial; microbial community; microbiome; microbiota; mortality; novel; prevent; respiratory; therapeutic target; therapy development

PROJECT SUMMARY/ABSTRACT Background and long-term objectives: This proposed research will advance our understanding of how the lung microbiome contributes to the pathogenesis and perpetuation of oxygen-induced lung injury. Inhaled oxygen is among our most commonly administered therapies. Yet hyperoxia - elevated inspired oxygen - causes lethal lung injury in animals, and in humans is associated with increased mortality and development of the acute respiratory distress syndrome. We have recently discovered that hyperoxia acutely alters lung microbiota. This oxygen-induced dysbiosis is strongly and temporally correlated with alveolar inflammation. We have discovered that germ-free mice - experimental mice devoid of microbiota - are protected from oxygen- induced lung injury, an observation that cannot be explained via our conventional model of oxygen-induced lung injury. Conversely, lung injury alters lung microbiota by changing bacterial growth conditions within the lung microenvironment. We have discovered that germ-free mice are protected from non-resolving lung injury (bleomycin), indicating that the microbiome is necessary for perpetuation of lung injury. The discovery of the lung microbiome has thus broadened our model of pathogenesis. The mechanisms by which lung microbiota mediate oxygen-induced lung injury, and are in turn altered by lung injury, are undetermined. The central hypothesis of this proposal is that specific bacteria within the lung ecosystem propel alveolar inflammation in oxygen-induced lung injury, and these bacteria are enriched within the lung microbiome both by hyperoxia itself and by the altered ecology of injured lungs. The rationale is that these discoveries will facilitate the development of therapies for the prevention and treatment of oxygen-related human lung disease. Specific Aim 1: To determine the microbial and molecular pathways by which oxygen therapy alters lung microbiota, mediating host inflammation and injury. We will accomplish this Aim by integrating complementary experimental approaches: in vivo heterogeneity analysis of host-microbiome interactions in mice; in vivo germ-free, gnotobiotic, and antibiotic-treated hyperoxia modeling in mice; data science interrogation of observational human data using a validated machine-learning algorithm. Specific Aim 2: To determine the molecular pathways by which oxygen-induced host inflammation and injury alter lung microbiota, perpetuating respiratory dysbiosis and lung injury. We will accomplish this Aim by integrating complementary experimental approaches: a novel ex vivo culture assay that identifies host- derived mediators of bacterial growth; in vivo augmentation and inhibition of the host response in hyperoxia. This translational research approach will determine 1) the key members of the lung microbiome that mediate oxygen-induced lung injury, 2) the pathways by which these bacteria promote alveolar inflammation, and 3) the ecologic factors within the injured lung environment that promote their growth.

项目摘要/摘要 背景和长期目标：这项拟议的研究将提高我们对如何 肺微生物组有助于氧诱导的肺损伤的发病机理和永久性。吸入 氧气是我们最常用的疗法之一。但是高氧 - 升高的氧气 - 导致动物致死性肺损伤，人类的死亡率和发展 急性呼吸窘迫综合征。我们最近发现高氧急性改变肺 微生物群。该氧气诱导的营养不良与肺泡炎症密切相关。我们 已经发现，无菌的无菌小鼠 - 没有菌群的实验小鼠受到保护 - 免受氧气的保护 诱导的肺损伤，这一观察结果无法通过我们的氧气传统模型来解释 肺部受伤。相反，肺损伤通过改变细菌生长条件来改变肺微生物群 肺微环境。我们发现无菌小鼠免受非分解肺损伤 （博来霉素），表明微生物组对于肺部损伤的持续性是必需的。发现 因此，肺微生物组扩大了我们的发病机理模型。肺微生物群的机制 介导氧诱导的肺损伤，而肺部损伤又不确定。 该提议的中心假设是肺生态系统内的特定细菌推动肺泡 氧诱导的肺损伤中的炎症，这些细菌富集在肺微生物组中 通过高氧本身以及受伤肺的生态改变。理由是这些发现将 有助于开发预防和治疗与氧相关的人肺疾病的疗法。 特定目的1：确定氧疗法改变的微生物和分子途径 肺微生物群，介导宿主炎症和损伤。我们将通过整合来实现这一目标 互补实验方法：宿主 - 微生物组相互作用的体内异质性分析 小鼠；小鼠中无体内细菌，gnotobiotic和抗生素处理的高氧建模；数据科学 使用经过验证的机器学习算法对观察性人数据进行询问。 特定目的2：确定氧诱导宿主炎症和的分子途径 损伤改变了肺微生物群，呼吸道断疾病和肺部损伤永存。我们将实现这一目标 通过整合互补的实验方法来实现目标：一种新型的离体培养测定法，可以识别宿主 - 衍生的细菌生长介体；体内增强和抑制高氧中宿主反应。 这种翻译研究方法将确定1）介导的肺微生物组的关键成员 氧诱导的肺损伤，2）这些细菌促进肺泡炎症的途径，3） 受伤的肺部环境中促进其生长的生态因素。