Exercise and Inflammation: Autonomic, Affective & Cellular Mechanisms

描述（由申请人提供）：有氧运动被广泛认为可以降低冠心病的风险，以至于共识小组经常建议将体育活动作为健康人群心脏保护方案的一部分。令人惊讶的是，这种保护的生理或机制基础尚不确定。一项研究表明，这种保护心脏的作用可能来自运动的抗炎作用，因为炎症在动脉粥样硬化的发病机制中起着核心作用。本申请旨在进行一项明确的研究，以确定有氧运动是否通过抑制炎症介质的产生来发挥心脏保护作用，其次，检查这种抑制是否通过增加迷走神经活动的机制。了解运动有益效果背后的机制是至关重要的，因为它将允许开发和测试有针对性的干预措施，以更直接地或在无法进行有氧运动的情况下产生类似的心脏保护作用。此外，它还可以导致运动在其他以这些潜在机制紊乱为特征的疾病中的治疗应用。因此，这个应用程序的潜在意义是巨大的。大量证据表明炎症与动脉粥样硬化有关，但有关运动和炎症的临床研究报道相对较少，这些研究的结论由于研究设计上的重大缺陷而受到影响。以往的研究通常以测量c反应蛋白（CRP）作为主要终点。虽然CRP很重要，但与急性期蛋白一样，它处于炎症介质级联反应的下游。肿瘤坏死因子（Tumor necrosis factor， TNF）位于该级联的上游，尽管有证据表明其在斑块稳定性、内皮功能障碍和动脉壁炎症损伤中发挥作用，但很少成为运动研究的重点。此外，许多研究本质上是横断面的。采用培训项目的研究通常缺乏对照组或只研究男性。我们的调查方法从几个方面解决了这些缺点。我们建议进行一项有氧运动与力量训练的随机对照试验，以测试在全血环境中对体外细胞生成TNF的影响。研究对象将是年轻、健康的久坐不动的男性和女性，在12周训练前后和4周久坐不动后进行研究。我们假设的证实将大大增加对体育锻炼益处的理解，并可能具有实质性的临床意义。公共卫生相关性：有氧运动——最广泛推荐的健康行为——被认为可以降低患冠心病的风险，以至于共识小组经常将其作为健康人心脏保护方案的一部分，但这种保护的生理或机制基础尚不确定。了解这些机制对公共卫生具有重要意义，因为它将允许开发和测试有针对性的干预措施，以更直接地或在不可能进行有氧运动的情况下产生类似的心脏保护作用。本研究旨在验证有氧训练导致LPS刺激下炎症反应减弱的假设，并检验运动诱导迷走神经活动增加、情绪改善和TLR4（单核细胞表达的内毒素同源受体）表达减少所起的作用。

DESCRIPTION (provided by applicant): Aerobic exercise is widely recognized to reduce the risk of coronary heart disease, so much so that consensus panels routinely recommend physical activity as part of a cardioprotective regimen for healthy people. Surprisingly, the physiological or mechanistic basis of this protection is uncertain. One line of investigation has examined the possibility that this cardioprotection derives from the anti-inflammatory effects of exercise, because inflammation occupies a central role in the pathogenesis of atherosclerosis. This application aims to conduct a definitive study to determine whether aerobic exercise exerts a cardioprotective effect by suppressing production of inflammatory mediators and, secondarily, to examine if this suppression is via a mechanism of increasing vagus nerve activity. Understanding the mechanisms that underlie the beneficial effects of exercise is essential because it will allow development and testing of targeted interventions to produce comparable cardioprotective effects more directly or in cases where aerobic exercise is not possible. Moreover, it can lead to the therapeutic application of exercise in other diseases characterized by disorders of these underlying mechanisms. Thus, the potential significance of this application is substantial. A large body of evidence implicates inflammation in atherosclerosis but relatively few clinical studies of exercise and inflammation have been reported, and the conclusions from these studies are tempered by significant shortcomings in study design. Previous investigations generally have measured C-reactive protein (CRP) as the major endpoint. Although important, CRP, like acute-phase proteins, is at the downstream end of the inflammatory mediator cascade. Tumor necrosis factor (TNF), more upstream in this cascade, is rarely the focus of exercise studies despite evidence suggesting its role in plaque stability, endothelial dysfunction, and inflammatory damage in the arterial wall. Additionally, many studies are cross- sectional in nature. Studies employing training programs typically lack control groups or study only men. Our approach to this investigation addresses these shortcomings in several ways. We propose to conduct a randomized controlled trial of aerobic exercise vs. strength training to test the impact on cell production of TNF ex vivo, in the whole blood milieu. Study subjects will be young, healthy sedentary men and women, studied before and after 12 weeks of training and again after 4 weeks of sedentary deconditioning. Confirmation of our hypotheses will add considerably to the understanding of the benefits of physical exercise and is likely to have substantial clinical significance. PUBLIC HEALTH RELEVANCE: Aerobic exercise - the most widely recommended health behavior - is recognized to reduce the risk of coronary heart disease, so much so that consensus panels routinely include it as part of a cardioprotective regimen for healthy people, but the physiological or mechanistic basis of this protection is uncertain. Understanding the mechanisms has considerable public health significance because it will allow development and testing of targeted interventions to produce comparable cardioprotective effects more directly or in cases where aerobic exercise is not possible. This application proposes to test the hypothesis that aerobic training leads to attenuation of the inflammatory response to LPS stimulation and to examine the role played by exercise-induced increases in vagal activity, improvements in mood, and decreased expression of TLR4, the cognate receptor for endotoxin expressed by monocytes.