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心脏保护养生方案的一部分。令人惊讶的是，这种保护的生理或机制基础是不确定的。一项调查研究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扮演着核心角色。这项应用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来实现。了解运动有益效果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，以更直接地产生类似的心脏保护效果，或者在有氧运动不可能的情况下产生类似的心脏保护效果。此外，它还可以导致运动在以这些潜在机制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。大量证据表明炎症与动脉粥样硬化有关，但关于运动和炎症的临床研究报道相对较少，这些研究的结论因研究设计的重大缺陷而受到影响。以往的研究一般将C反应蛋白(CRP)作为主要终点。虽然很重要，但CRP和急性期蛋白一样，处于炎症介质级联反应的下游。尽管有证据表明，肿瘤坏死因子(TNF)在斑块稳定、内皮功能障碍和动脉壁炎症损伤中发挥作用，但在这一级联中更上游的肿瘤坏死因子(TNF)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。采用培训计划的研究通常没有控制组，或者只研究男性。我们对这项调查的方法从几个方面解决了这些缺陷。我们建议进行有氧运动和力量训练的随机对照试验，以测试在体外全血环境中肿瘤坏死因子对细胞产生的影响。研究对象将是年轻、健康的久坐不动的男性和女性，他们在12周的训练之前和之后进行研究，并在4周的久坐解除条件后再次进行研究。证实我们的假设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。与公共健康相关：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，以更直接地或在不可能进行有氧运动的情况下产生类似的心脏保护效果。这项应用建议测试有氧训练导致对内毒素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、情绪改善以及单核细胞表达内毒素的同源受体TLR4的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.