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

项目摘要/摘要 背景和长期目标：这项拟议的研究将促进我们对 肺微生物群参与了氧性肺损伤的发生和延续。吸入 氧气是我们最常用的治疗方法之一。然而，高氧-升高的吸入氧气- 在动物中引起致命性肺损伤，在人类中与死亡率增加和 急性呼吸窘迫综合征。我们最近发现高氧对肺部有很大的影响。 微生物区系。这种氧诱导的生物失调与肺泡炎有很强的时间相关性。我们 已经发现，无菌小鼠--缺乏微生物区系的实验小鼠--可以免受氧气的伤害-- 致肺损伤，这一观察结果不能用我们传统的氧致伤模型来解释 肺损伤。相反，肺损伤通过改变肺内细菌的生长条件来改变肺微生物区系。 肺微环境。我们发现，无菌小鼠可以免受未消退的肺损伤。 (博莱霉素)，这表明微生物群对于肺损伤的持久存在是必要的。人类的发现 因此，肺微生物组拓宽了我们的致病模式。肺微生物区系的作用机制 介导氧诱导的肺损伤，并继而被肺损伤改变，目前还不确定。 这一建议的中心假设是，肺部生态系统内的特定细菌推动肺泡 氧致肺损伤中的炎症，而这些细菌在肺内都富含微生物 由高氧本身和受损肺的生态改变所致。理由是这些发现将 促进开发预防和治疗与氧气有关的人类肺部疾病的治疗方法。 具体目标1：确定氧疗改变的微生物和分子途径 肺部微生物区系，介导宿主炎症和损伤。我们将通过整合 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；体内无菌、生药和抗生素治疗的小鼠高氧模型；数据科学 使用经过验证的机器学习算法对观察到的人类数据进行询问。 特定目标2：确定氧诱导宿主炎症和 损伤改变了肺微生物区系，使呼吸失调和肺损伤永久化。我们会做到这一点的 目的通过整合互补的实验方法：一种新的体外培养方法来鉴定宿主- 细菌生长的衍生介质；体内高氧时宿主反应的增强和抑制。 这种转译研究方法将确定1)肺微生物组的关键成员 氧致肺损伤，2)这些细菌促进肺泡炎的途径，以及3) 受损肺环境中促进其生长的生态因素。

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.