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: 10426021
• 负责人: Robert Pickett Dickson
• 金额: $ 43.42万
• 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/10426021
• 关键词: Acute; Acute 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; 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.

项目总结/摘要 背景和长期目标：这项拟议中的研究将促进我们对 肺微生物组有助于氧诱导的肺损伤的发病机制和持续。吸入 氧气是我们最常用的治疗方法之一。但是高氧-吸入的氧气量增加- 在动物中导致致命的肺损伤，在人类中与死亡率增加和 急性呼吸窘迫综合征我们最近发现，高氧会急性改变肺 微生物群这种氧诱导的生态失调与肺泡炎症强烈且暂时相关。我们 发现无菌小鼠--没有微生物群的实验小鼠--可以免受氧气的影响， 诱导的肺损伤，这一观察结果无法通过我们的传统氧诱导肺损伤模型来解释。 肺损伤相反，肺损伤通过改变肺内的细菌生长条件来改变肺微生物群。 肺微环境我们已经发现无菌小鼠可以避免非解决性肺损伤 （博来霉素），表明微生物组对于肺损伤的持续是必需的。的发现 因此，肺部微生物组拓宽了我们的发病机制模型。肺部微生物群 介导的氧诱导的肺损伤，并反过来改变肺损伤，是不确定的。 这一建议的中心假设是，肺生态系统中的特定细菌推动肺泡 氧诱导的肺损伤中的炎症，这些细菌在肺微生物组中富集， 由于高氧本身和受伤肺部生态的改变。理由是，这些发现将 促进开发用于预防和治疗氧相关的人类肺病的疗法。 具体目标1：确定氧疗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 互补实验方法：在体内宿主-微生物组相互作用的异质性分析 小鼠;小鼠体内无菌、无菌和无菌处理的高氧模型;数据科学 使用经验证的机器学习算法询问观察到的人类数据。 具体目标2：确定氧诱导的宿主炎症和炎症反应的分子途径。 损伤改变肺微生物群，使呼吸系统生态失调和肺损伤永久化。我们会完成的 目的通过整合互补的实验方法：一种新的体外培养试验， 细菌生长的衍生介质;体内增强和抑制宿主对高氧的反应。 这种转化研究方法将确定1）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，以及3） 促进其生长的受损肺环境中的生态因素。