Respiratory muscle work and oxidative stress in COPD: impact on leg blood flow an

描述(由申请人提供)：COPD患者的日常活动受到限制，因为运动限制可能会严重到损害简单的日常任务。这项拟议的研究将检查可能导致运动耐量严重受限的新机制，并确定如何提高运动耐量。具体地说，我们将评估过度呼吸肌工作的作用，这是COPD患者的特征，以及运动期间氧化应激增加在这一人群中的作用。此外，我们将评估呼吸功的增加是否是COPD患者运动期间氧化应激水平增加的重要因素。我们将a)使用机械呼吸机和降低密度的混合气体来减少自行车运动中的呼吸功，以及b)在自行车运动中使用静脉注射维生素C来检查呼吸功减少和氧化应激减少对锻炼腿部肌肉疲劳的影响。我们将使用一种新的方法组合来提供一种灵敏的、可重复的、客观的量化四肢肌肉疲劳的方法。我们将进一步研究这些对肢体疲劳的拟议影响是否部分是由于血液流动和氧气(O2)输送到肢体，以及呼吸和氧化应激对此有何影响。在健康的受试者中，已有研究表明，呼吸肌作功的减少会增加血液流量，并将氧气输送到四肢。同样在健康的受试者中，我们最近发现，增加流向工作腿的血流量/氧气运输显著减少肌肉疲劳，提高运动耐力。此外，已有研究表明，氧化应激的减少也会增加老年健康人在运动时的血流量/氧气输送，然而，目前还没有关于氧化应激对COPD患者运动期间肢体血流/氧气输送的影响的数据。鉴于运动中所需的呼吸功显著增加，COPD患者的氧化应激显著增加，我们预计减少这些因素对四肢肌肉疲劳的影响的效果将比健康受试者更大。我们认为，这项研究将为COPD患者在康复过程中提高运动能力提供新的有效方法，使他们能够提高运动肌肉的耐力。预计康复过程的这一改进将防止肌肉功能恶化，而肌肉功能恶化目前在久坐不动的慢性阻塞性肺病人群中很普遍。 公共卫生相关性：我们认为，这项研究将为COPD患者在康复期间提高运动能力提供新的有效方法，使他们能够提高运动(腿部)肌肉的耐力。预计康复过程的这一改进将防止肌肉功能恶化，而肌肉功能恶化目前在久坐不动的慢性阻塞性肺病人群中很普遍。

DESCRIPTION (provided by applicant): Patients with COPD are limited in their daily activities because of exercise limitation that can be sufficiently severe to impair simple everyday tasks. The proposed research will examine novel mechanisms that might contribute to this severe limitation in exercise tolerance and also determine how exercise tolerance might be improved. Specifically, we will assess the role of excessive respiratory muscle work, a characteristic of COPD patients, and elevated oxidative stress during exercise in this population. Additionally, we will assess whether the increased work of breathing is a significant contributor to the increased levels of oxidative stress during exercise in patients with COPD. We will a) use a mechanical ventilator in combination with a reduced density gas mixture to reduce the work of breathing during cycle exercise and b) use venous infusion of vitamin C during cycle exercise to examine the effects of both, the reduced work of breathing and the reduced oxidative stress on muscle fatigue in the exercising legs. We will use a novel combination of methods to provide a sensitive, reproducible, objective means of quantifying limb muscle fatigue. We will further examine whether these proposed effects on limb fatigue are, in part, due to blood flow and oxygen (O2) transport to the limbs and how this is influenced by the work of breathing and oxidative stress. In healthy subjects it has been shown that a reduction in respiratory muscle work increases blood flow and O2 transport to the limbs. Also in healthy subjects, we have recently revealed that increases in blood flow / O2 transport to the working legs significantly reduces muscle fatigue and improves exercise tolerance. Furthermore, it has been shown that a reduction in oxidative stress also increases blood flow / O2 delivery during exercise in older healthy individuals, however, there are currently no data on the effects of oxidative stress on limb blood flow / O2 transport in COPD patients during exercise. In view of the significantly increased work of breathing required during exercise and the substantially increased oxidative stress in COPD patients, we expect the effects of reducing the impact of these factors on limb muscle fatigue to be even greater than in healthy subjects. We propose that this research will provide new effective methods to improve exercise capacity during the rehabilitation of patients with COPD by allowing them to improve endurance of their locomotor muscles. It is anticipated that this improvement in the rehabilitation process will prevent the deterioration of muscle function which is currently prevalent in the sedentary COPD population. PUBLIC HEALTH RELEVANCE: We propose that this research will provide new effective methods to improve exercise capacity during the rehabilitation of patients with COPD by allowing them to improve endurance of their locomotor (leg) muscles. It is anticipated that this improvement in the rehabilitation process will prevent the deterioration of muscle function which is currently prevalent in the sedentary COPD population.