Muscle dysfunction in COPD The role of oxidative stress

虽然慢性阻塞性肺疾病的病因和治疗很复杂，而且仍然有些模糊，但最近的研究 关注慢性阻塞性肺病的外周后果已经开始确定导致 这种疾病对心血管系统和骨骼肌的有害影响。 骨骼肌功能障碍常常导致体力活动受限和随后的发育。 心血管疾病，这是慢性阻塞性肺疾病患者发病的主要原因。一个对肌肉有贡献的人 与COPD相关的功能障碍和恶病质是氧化应激，定义为体内 以及有利于前者的抗氧化剂分子种类。自由基生成是一种无处不在的 新陈代谢的结果，据推测，COPD， 运动中的氧化应激和肌肉功能障碍。然而，到目前为止，还没有研究尝试直接 测量自由基，以确定氧化应激在这种疾病中的影响。因此，使用一个 敏锐地意识到COPD潜在特征的重要性和多样性，我们提出了一系列 更好地了解COPD骨骼肌中氧化应激的作用和来源的研究 既有恶病质表型又没有恶病质表型的患者。四个具体目标将解决以下问题 关于慢性阻塞性肺疾病、骨骼肌和氧化应激：氧化应激在哪里最普遍，为什么 氧化应激的发生，氧化应激的后果是什么，运动是如何诱导的 慢性阻塞性肺疾病患者的氧化应激影响训练反应？需要检验的总体假设是，这种转变 COPD患者肌肉内更大的氧化应激至少在一定程度上是导致 工作中机械效率降低、恶病质和肌肉相关的运动受限 与这种疾病有关的。具体地说，通过使用电子顺磁直接检测自由基 骨骼肌和静脉-动脉的共振(EPR)波谱和抗氧化剂测定 肌肉床上的差异，我们将确定肌肉和肌肉中是否存在COPD相关的差异 运动过程中的血管隔间。用同样的方法结合一位简化论者 我们将确定新陈代谢、切应力和机械运动对 肌肉床内的自由基和抗氧化剂之间的平衡。最后，我们将利用外源 抗氧化剂和运动训练，以直接记录COPD和自由基对NO的影响， 一种新的测量血管生长因子、运动训练和血流与新陈代谢匹配的方法 磁共振成像方法学。结合起来，这些研究将提供具有临床意义的 了解氧化应激、骨骼肌功能和血管健康在慢性阻塞性肺疾病中的作用。

While the etiology and treatment of COPD is complex and remains somewhat poorly defined, recent studies focusing on the peripheral consequences of COPD have begun to define the mechanisms responsible for the detrimental impact on the cardiovascular system and skeletal muscle which occur with this disease. Skeletal muscle dysfunction often leads to limitations in physical activity and to the subsequent development of cardiovascular disease, a major cause of morbidity in patients with COPD. One contributor to the muscle dysfunction and cachexia associated with COPD is oxidative stress, defined as an imbalance between pro and antioxidant molecular species in favor of the former. Free radical generation is a ubiquitous consequence of metabolism and it has been postulated that there maybe a mechanistic link between COPD, oxidative stress, and muscle dysfunction during exercise. However, to date no studies have attempted direct measurements of free radicals to determine the impact of oxidative stress in this disease. Thus, with an acute awareness of the importance and diversity of the potential COPD characteristics we propose a series of studies to better understand the role and source of oxidative stress in the skeletal muscle of COPD patients both with and without a cachectic phenotype. Four specific aims will address the following questions regarding COPD, skeletal muscle, and oxidative stress: Where is oxidative stress most prevalent, why does oxidative stress occur, what are the consequences of oxidative stress, and how does exercise-induced oxidative stress impact training responses in COPD? The overall hypothesis to be tested is that the shift toward greater intramuscular oxidative stress in COPD is, at least in part, responsible for the diminished mechanical efficiency, cachexia, and muscle related exercise limitation during work often associated with this disease. Specifically, by direct free radical detection using electron paramagnetic resonance (EPR) spectroscopy and antioxidant measurements in skeletal muscle and venous-arterial difference across the muscle bed, we will determine if there are COPD-related differences in the muscle and vascular compartments during exercise. With these same methods in combination with a reductionist approach we will determine the contribution of metabolism, shear stress and mechanical movement to the balance between free radicals and antioxidants within the muscle bed. Finally, we will utilize exogenous antioxidants and exercise training to directly document the impact of COPD and free radicals on NO, vascular growth factors, exercise training and the matching of blood flow to metabolism measured by a novel magnetic resonance imaging methodology. In combination these studies will provide clinically significant insight into the role of oxidative stress, skeletal muscle function, and vascular health in COPD.