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推荐体力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是不确定的。一条研究线已经检查了这种心脏保护来自运动的抗炎作用的可能性，因为炎症在动脉粥样硬化的发病机制中占据中心作用。本申请旨在进行确定性研究，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，检查这种抑制是否是通过增加迷走神经活动的机制。了解运动有益作用的机制至关重要，因为它将允许开发和测试有针对性的干预措施，以更直接地或在有氧运动不可能的情况下产生可比的心脏保护作用。此外，它可以导致运动在以这些潜在机制的紊乱为特征的其他疾病中的治疗应用。因此，这一应用的潜在意义是巨大的。大量证据表明动脉粥样硬化与炎症有关，但有关运动和炎症的临床研究报道相对较少，而且这些研究的结论因研究设计中的重大缺陷而受到影响。以前的研究通常将C反应蛋白（CRP）作为主要终点。虽然重要，CRP，像急性时相蛋白，是在下游端的炎症介质级联反应。肿瘤坏死因子（TNF），在这个级联反应中更上游，很少是运动研究的重点，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性损伤中的作用。此外，许多研究是横向的性质.采用培训项目的研究通常缺乏对照组或仅研究男性。我们的调查方法以几种方式解决了这些缺点。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离体TNF对细胞产生的影响。研究对象是年轻、健康的久坐男性和女性，在12周的训练之前和之后进行研究，并在4周的久坐去适应后再次进行研究。证实我们的假设将大大增加对体育锻炼的好处的理解，并可能具有重大的临床意义。公共卫生相关性：有氧运动-最广泛推荐的健康行为-被认为可以降低冠心病的风险，以至于共识小组通常将其作为健康人群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。了解这些机制具有相当大的公共卫生意义，因为它将允许开发和测试有针对性的干预措施，以更直接地或在有氧运动不可能的情况下产生可比的心脏保护作用。本申请提出测试有氧训练导致对LPS刺激的炎症反应减弱的假设，并检查运动诱导的迷走神经活动增加、情绪改善和TLR 4（单核细胞表达的内毒素的同源受体）表达降低所起的作用。

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.