Immune, hormonal, and muscle mitochondrial determinants of recovery in Acute Respiratory Distress Syndrome survivors

项目总结 在新冠肺炎之前，每年有超过150,000名美国人在急性呼吸窘迫综合征中幸存下来。 到目前为止，已有50多万美国人在新冠肺炎ARDS中幸存下来。至少一半的ARDS幸存者 持续性肌肉无力，导致残疾、医疗费用和死亡率增加。没有 改善ARDS幸存者肌肉力量和身体恢复的靶向治疗，因为 这些身体损伤和恢复不良背后的机制还没有被很好地理解。整体而言 该项目的假设是，在急性ARDS中发生的多系统失调在住院后持续存在 在那些有持续性身体损伤的人中出院，在那些身体恢复的人中解决。整体而言 该项目的目标是确定来自调节失调的单核细胞、合成代谢的持续性炎症 激素缺乏和出院后3个月的肌肉线粒体功能障碍 急性呼吸窘迫综合征幸存者肢体残疾的治疗目标。为了实现我们的目标，我们将进行嵌套 队列病例对照研究。我们将前瞻性地招募345名出院的ARDS幸存者，其中12人- 从约翰霍普金斯大学和哥伦比亚大学医院进行了一个月的纵向随访。三个月 出院后，我们将对180名ARDS幸存者进行面对面嵌套病例对照研究， 病例状态定义为未从新的残疾中恢复。炎症，合成激素缺乏，以及 肌肉线粒体功能障碍随着年龄和合并症的增加而增加，老年ARDS幸存者较少 比那些更年轻、更健康的人更有可能康复。因此，要确定生物标志物水平和肌肉 与ARDS相关的线粒体功能障碍，与年龄或合并症无关，我们将比较 ARDS幸存者与来自国家心肺和血液中心的精心配对的社区成年人 (NHLBI)动脉粥样硬化多种族研究(MESA)和哥伦比亚大学梅里特中心 肌肉生物库。在整个队列中，我们仔细地协调了社会人口、临床和功能 评估，以便于仔细匹配。我们将进行严格的血清生物标志物评估，有针对性地 血浆代谢组学、血液高维流式细胞术和肌肉活检线粒体功能和 基因表达分析以实现我们的三个目标：(1)确定单核细胞功能在 ARDS幸存者的残疾恢复；(2)确定合成代谢激素缺乏在恢复中的作用 ARDS幸存者的残疾；以及(3)确定线粒体肌病的血浆生物标志物 与ARDS幸存者的骨骼肌线粒体功能障碍和残疾恢复有关。这个 总体目标是进行表观机制研究，为未来ARDS后的靶向随机试验提供信息 抗炎疗法、激素补充疗法和肌肉线粒体疗法 为了改善ARDS幸存者的身体功能，NHBLI的研究重点。

PROJECT SUMMARY Prior to COVID-19, over 150,000 Americans survived Acute Respiratory Distress Syndrome (ARDS) each year. To date, more than 500,000 Americans have survived COVID-19 ARDS. At least half of ARDS survivors have persistent muscle weakness that results in increased disability, healthcare costs, and mortality. There are no targeted therapies to improve muscle strength and physical recovery in ARDS survivors, because the mechanisms underlying these physical impairments and poor recovery are not well understood. The overall hypothesis of the project is that multi-systemic dysregulation that occurs in acute ARDS, persists after hospital discharge in those with persistent physical impairment, and resolves in those who recover physically. The overall objective of the project is to determine whether persistent inflammation from dysregulated monocytes, anabolic hormone deficiencies, and muscle mitochondrial dysfunction at 3 months after hospital discharge are each treatment targets for physical disability in ARDS survivors. To achieve our objective, we will conduct a nested case-control study of cohorts. We will prospectively enroll 345 ARDS survivors at hospital discharge with 12- month longitudinal follow-up from Johns Hopkins University and Columbia University hospitals. Three months after hospital discharge, we will conduct an in-person nested case-control study of 180 ARDS survivors, with case status defined as not-recovered from new disability. Inflammation, anabolic hormone deficiencies, and muscle mitochondrial dysfunction increase with aging and comorbidity, and older adult ARDS survivors are less likely to recover than those who are younger and healthier. Therefore, to determine biomarker levels and muscle mitochondrial dysfunction that are associated with ARDS, independent of age or comorbidity, we will compare ARDS survivors with carefully matched community-dwelling adults from the National Heart Lung and Blood Institute (NHLBI) Multi-Ethnic Study of Atherosclerosis (MESA) and the Columbia University Merritt Center muscle biobank. Across the cohorts, we have carefully coordinated sociodemographic, clinical, and functional assessments to facilitate careful matching. We will conduct rigorous serum biomarker assessments, targeted plasma metabolomics, high dimensional flow cytometry of blood, and muscle biopsy mitochondrial function and gene expression analyses to accomplish our three Aims: (1) to determine the role of monocyte function in recovery from disability in ARDS survivors; (2) to determine the role of anabolic hormone deficiencies in recovery from disability in ARDS survivors; and (3), to determine how plasma biomarkers of mitochondrial myopathy associate with skeletal muscle mitochondrial dysfunction and recovery from disability in ARDS survivors. The overall goal is to conduct epi-mechanistic studies that will inform future post-ARDS randomized trials of targeted anti-inflammatory therapies, hormone supplementation therapies, and muscle mitochondrial therapies that aim to improve physical function in ARDS survivors, a NHBLI research priority.