Effects of Exercise on Inflammation-Induced Lung and Muscle Injury in Critical Illness (NEXIS-FLAME)

项目摘要 早期活动，即在临床护理期间让患者参与锻炼和/或物理治疗的过程， 是一种很有前途的治疗严重的危重病，如急性呼吸衰竭（ARF），其中， 改善各种临床和功能结果。早期的流动性/锻炼如何带来这些好处， 然而，它是未知的，研究不足。这种知识的缺乏是值得注意的，因为 在这些人群中进行锻炼/活动干预是极具挑战性和资源密集型的。 了解早期流动/锻炼的有益效果的机制， 特定的细胞和分子靶点，使临床医生能够改进干预措施， 在资源和人员限制应用的环境中开发运动模拟疗法 经典的移动/运动干预。为了解决这一知识差距，我们在此应用程序中的目标是 确定运动调节全身和终末器官炎症和损伤的机制 在ARF。我们将使用反向和正向翻译的方法来实现这一目标，建立在我们的前， 肺损伤患者早期活动性的临床模型和人体数据。基于强有力的初步数据 从这些来源，我们提出了一个假设的模型，其中全身炎症反应期间， 通过IL-17/G-CSF轴介导的危重病的早期阶段导致肺损伤和骨骼肌损伤， 继发于免疫细胞浸润和炎症的消耗。此外，在此阶段应用的练习 通过特异性减弱全身和局部先天性免疫减少终末器官损伤/消耗 应答我们将利用NHLBI资助的一项研究， 早期运动和氨基酸的随机对照试验（NEXIS RCT，R 01 HL 132887，NCT 03021902） 在ARF危重患者以及精心选择动物中补充与常规护理的比较 模型来扩展我们的洞察力。由于NEXIS RCT于2017年9月开始招募，我们希望 目前的应用程序将得到资助，使我们能够捕捉大多数NEXIS参与者的关键 生物标本采集。我们预计，我们的结果将产生开创性的，机械的知识， 运动对减少全身和终末器官炎症以及肺和骨骼炎症的有益作用 肌肉损伤我们的研究结果也有可能确定一种新的机制，运动的系统性 通过调节一种新的肌因子，改变全身和局部炎症反应的好处。 因此，我们的发现将推动基础科学知识和临床实践朝着以下目标发展： 改善危重病患者和其他患者的短期临床和长期功能结局 炎性条件。

Project Summary Early mobility, the process of engaging patients in exercise and/or physical therapy during their clinical care, is a promising treatment for severe critical illnesses, such as acute respiratory failure (ARF), where it improves a variety of clinical and functional outcomes. How early mobility/exercise exacts these benefits, however, is unknown and understudied. This lack of knowledge is notable because the implementation of exercise/activity interventions in these populations is extremely challenging and resource intensive. Knowledge of the mechanisms underlying the beneficial effects of early mobility/exercise would provide specific cellular and molecular targets that would allow clinicians to refine interventions and stimulate development of exercise-mimetic therapeutics in settings where resources and personnel limit the application of classical mobility/exercise interventions. To address this knowledge gap, our goal in this application is to determine the mechanisms whereby exercise modulates systemic and end organ inflammation and damage in ARF. We will use reverse and forward translational approaches to realize this goal, building on our pre- clinical model of early mobility and human data in patients with lung injury. Based on strong preliminary data from these sources, we propose a hypothetical model in which a systemic inflammatory response during the early phase of critical illness, mediated via the IL-17/G-CSF axis, causes lung injury and skeletal muscle wasting secondary to immune cell infiltration and inflammation. Moreover, exercise applied during this phase lessens end-organ injury/wasting by specifically attenuating the systemic and local innate immune responses. We will examine these hypotheses in critically ill humans by leveraging an NHLBI-funded randomized controlled trial (NEXIS RCT, R01HL132887, NCT03021902) of early exercise and amino acid supplementation versus usual care in critically ill patients with ARF, as well as carefully selected animal models to extend our insights. As, the NEXIS RCT began recruitment in September 2017, we hope that the current application will be funded allowing us to capture most of the NEXIS participants for crucial biospecimen collection. We anticipate that our results will yield seminal, mechanistic knowledge of the beneficial effects of exercise to reduce systemic and end organ inflammation and, in turn, lung and skeletal muscle damage. Our results also hold the potential to identify a novel mechanism of exercise's systemic benefits through modulation of a novel myokine that alters the systemic and local inflammatory response. Our findings, therefore, will advance both basic scientific knowledge and clinical practice towards the goal of improving short-term clinical and long-term functional outcomes in patients with critical illness and other inflammatory conditions.