Targeting metabolic pathways in lung injury

项目总结 急性呼吸窘迫综合征(ARDS)影响着美国20多万人和300多万人 每年在全球范围内。这种高度致命的综合征可能是由于各种类型的肺损伤(例如 肺炎、吸入性损伤或败血症)。30%到40%的患有这种疾病的患者会死亡--通常 多器官衰竭的症状。目前还没有可用的药物治疗ARDS，治疗基本上是 支持我。因此，迫切需要针对这种情况的新疗法。急性呼吸窘迫综合征的病理生理研究 已经表明，肺损伤是高度炎症的，但有许多不同的抗炎疗法 已经在临床试验中进行了测试，但未能降低这种疾病的死亡率。一种潜在的新方法 治疗ARDS可以在免疫代谢的新生领域找到，这表明激活 免疫细胞(如已知在ARDS中起重要作用的肺巨噬细胞和中性粒细胞) 导致重要的代谢变化，这是支持促炎反应所必需的。了解 支持急性肺损伤期间有害炎症的代谢途径可能导致治疗 通过调节新陈代谢加速炎症消退和促进伤口愈合的不良反应。 在这项提案中，在肺损伤过程中改变的代谢途径也将在动物模型中进行研究。 就像人类的生物群落一样。我们的初步数据显示，两种特殊的代谢物-肌醇和肌醇 谷胱甘肽--在三种不同的急性肺损伤动物模型中，谷胱甘肽含量迅速下降。此外，治疗 在我们的一个模型中，小鼠患有肌醇或谷胱甘肽-肺炎链球菌肺炎，也 被称为“肺炎球菌”--极大地提高了它们的存活率。肌醇和谷胱甘肽都可以作为 抗氧化剂，所以我们假设它们在肺损伤过程中由于氧化应激而耗尽。 补充这些代谢物可以通过减少肺炎球菌感染期间的死亡率来提高存活率 氧化损伤。在本项目的目标1中，肌醇和谷胱甘肽变化的细胞基础 将通过分离免疫细胞和非免疫细胞(例如内皮细胞和上皮细胞)来检查新陈代谢 细胞)，并测量这些细胞中的代谢物丰度 分离的细胞群。在目标2中，我们将检查肌醇或谷胱甘肽对小鼠的治疗 降低肺炎球菌肺炎模型中的氧化应激水平，以及这是否与 减少炎症和肺损伤。在目标3中，我们将测量未识别的代谢物的水平 新冠肺炎肺炎致急性呼吸窘迫综合征患者支气管肺泡灌洗液标本与对照组的比较 健康对照组，以确定肌醇和谷胱甘肽水平是否在人类ARDS期间下降 我们的老鼠模型。完成这个项目将提供对ARDS生物学的基本见解，并可能 可能会导致这种致命疾病的新疗法。它还将为申请者提供一个机会 培养成为一名成功的内科科学家所需的技能。

PROJECT SUMMARY Acute respiratory distress syndrome (ARDS) affects over 200,000 individuals in the US and over 3 million worldwide each year. This highly lethal syndrome can occur due to various types of lung injury (for example pneumonia, inhalational injury, or sepsis). Thirty to forty percent of patients with this condition will die – usually of multiorgan failure. There are no available pharmacologic therapies for ARDS and treatment is essentially supportive. Novel therapies for this condition are therefore urgently needed. Studies of ARDS pathophysiology have shown that lung injury is highly inflammatory, but numerous different anti-inflammatory therapies that have been tested in clinical trials have failed to reduce mortality from this disease. A potential novel approach to treating ARDS may be found in the nascent field of immunometabolism, which has shown that activation of immune cells (such as the lung macrophages and neutrophils that are known to play an important role in ARDS) leads to major metabolic changes that are necessary to support pro-inflammatory responses. Understanding the metabolic pathways that support detrimental inflammation during acute lung injury could lead to treatments for ARDS that hasten resolution of inflammation and promote wound healing through modulation of metabolism. In this proposal, metabolic pathways that are altered during lung injury will be studied in animal models as well as in human biospecimens. Our preliminary data has shown that two particular metabolites–myo-inositol and glutathione—rapidly drop in abundance in three different animals models of acute lung injury. Moreover, treating mice with myo-inositol or glutathione in one of our models—pneumonia due to Streptococcus pneumoniae, also known as “pneumococcus”—significantly improved their survival. Myo-inositol and glutathione can both act as antioxidants, so we hypothesize that they are depleted during lung injury because of oxidative stress. Supplementation with these metabolites may improve survival during pneumococcal infection by reducing oxidative injury. In Aim 1 of this project, the cellular basis of the changes in myo-inositol and glutathione metabolism will be examined by separating immune cells and non-immune cells (e.g. endothelial and epithelial cells) from the lungs of mice with pneumococcal pneumonia and measuring metabolite abundance in these separated cell populations. In Aim 2, we will examine whether treatment of mice with myo-inositol or glutathione reduces levels of oxidative stress in the pneumococcal pneumonia model and whether this correlates with reduced inflammation and lung injury. In Aim 3, we will measure levels of metabolites in de-identified bronchoalveolar lavage fluid samples from patients with ARDS due to COVID-19 pneumonia compared to healthy controls to determine whether myo-inositol and glutathione levels fall during human ARDS as they do in our mouse models. Completing this project will provide fundamental insights into the biology of ARDS and could potentially lead to novel therapies for this deadly disease. It will also provide the applicant with an opportunity to develop skills needed to become a successful physician-scientist.