Exercise-enhanced resolution of inflammation

摘要： 经常运动可改善心血管健康并延长寿命，而不运动则 与过早死亡和慢性病的全球负担有关。锻炼的有益效果是 在文献中有广泛的记载。运动促进骨骼肌生长、心肌肥大和组织 血管生成，改善心血管疾病(CVD)风险因素概况。尽管如此， 运动超越了降低心血管危险因素(血压、血脂)的范围，涉及以下机制和过程 在很大程度上仍然不为人知。缺乏对运动有益效果的机械论理解，限制了它 在健康的个人中进行优化，并阻碍其益处扩展到肥胖和糖尿病患者，尽管 最有可能从锻炼中获益的人，不能锻炼或不受其好处影响的人。一些调查人员已经 提示运动对心血管疾病危险因素的非依赖性影响可能与炎症的减少有关。炎症 是一种精心策划的系统性反应，旨在降解有害成分，清除组织碎片，促进 治愈和恢复动态平衡。而炎症的升级导致炎症细胞的侵袭和细胞因子 对产物进行了广泛的研究，但对炎症如何消退知之甚少。最近的研究表明 炎症的消退是由限制中性粒细胞的特殊的促分解脂质介体(SPM)介导的 外渗，平息炎症信号，促进巨噬细胞吞噬。SPM是必要的也是充分的 通过与同源G蛋白偶联受体(GPCRs)结合来消炎。我们建议，受益的 运动的作用与其通过刺激促分解因子的合成来促进炎症消退的能力有关 SPM。我们的初步数据显示，运动适应的小鼠表现出SPM合成增加，中性粒细胞加速 清除和巨噬细胞吞噬增加，表明运动对解决 发炎。我们还发现，运动中短暂升高的儿茶酚胺能激活SPM的生物合成。 并增加合成SPM的5-脂氧合酶(5-LO)和12/15-脂氧合酶(15-LO)。 这些观察将运动激活的过程与炎症消退的关键组成部分联系起来，并引导我们 提出运动介导的儿茶酚胺产生增加促分解脂质介质的假说 合成并提高炎症的消退能力。具体目的是：(1)确定运动对人的影响 (2)描述儿茶酚胺在调节运动对运动的影响中的作用。 炎症反应；(3)阐明SPM在运动增强的分解中的作用。该项目的成果将产生新的 对运动如何调节炎症；哪些过程调节运动的有益效果；以及如何 运动会影响急性和慢性炎症的消退。总的来说，这些结果将产生新的知识 关于运动改善心脏代谢健康和消炎的过程。这一知识可能会 导致新的治疗干预措施的发展，以增强锻炼的益处或模拟其有益效果 对其有益效果具有抵抗力或顽固性的个人，或无法锻炼的人。

Abstract: Frequent physical activity improves cardiovascular health and prolongs life span, whereas physical inactivity is associated with premature mortality and global burden of chronic disease. The salutary effects of exercise have been extensively documented in the literature. Exercise promotes skeletal muscle growth, cardiac hypertrophy, and tissue angiogenesis and it improves cardiovascular disease (CVD) risk factor profile. Nevertheless, the beneficial effects of exercise extend beyond reduction in CVD risk factors (blood pressure, lipids) involving mechanisms and processes that remain largely unknown. This lack of mechanistic understanding underlying the salubrious effects of exercise limits its optimization in healthy individuals, and hinders extension of its benefits to obese and diabetic individuals, who though are most likely to gain from exercise, cannot exercise or remain impervious to its benefits. Some investigators have suggested that CVD risk factor-independent effects of exercise may relate to a decrease in inflammation. Inflammation is a carefully orchestrated systemic response targeted to degrade offending components, clear tissue debris, promote healing and restore homeostasis. While escalation of inflammation leading to inflammatory cell invasion and cytokine production has been extensively studied, less is known about how inflammation is resolved. Recent work has shown that resolution of inflammation is mediated by specialized pro-resolving lipid mediators (SPMs) that limit neutrophil extravasation, quell inflammatory signaling, and promote macrophage phagocytosis. SPMs are necessary and sufficient to resolve inflammation by binding to cognate G-protein coupled receptors (GPCRs). We propose that the beneficial effects of exercise relate to its ability to promote resolution of inflammation by stimulating the synthesis of pro-resolving SPMs. Our preliminary data show that exercise-adapted mice display enhanced SPM synthesis, accelerated neutrophil clearance and increased macrophage phagocytosis, suggesting that exercise exerts beneficial effects on resolution of inflammation. We also find that catecholamines, which are transiently elevated by exercise, activate SPM biosynthesis in macrophages and increase 5-lipoxygenase (5-LO) and 12/15-lipoxygenase (15-LO), enzymes that synthesize SPMs. These observations link processes activated by exercise to key components of inflammation-resolution and have led us to formulate the hypothesis that exercise-mediated production of catecholamines increases pro-resolving lipid mediator synthesis and enhances resolution of inflammation. The specific aims are: (1) Determine the effect of exercise on resolution; (2) Delineate the contribution of catecholamines in mediating the effect of exercise on resolution of inflammation; (3) Elucidate the role of SPMs in exercise-enhanced resolution. Results of this project will generate new insights into how exercise regulates inflammation; which processes mediate the beneficial effects of exercise; and how exercise affects the resolution of acute and chronic inflammation. Collectively, these results would generate new knowledge about the processes by which exercise improves cardiometabolic health and inflammation-resolution. This knowledge could lead to the development of new therapeutic interventions to enhance the benefits of exercise or simulate its salutary effects in individuals resistant or recalcitrant to its beneficial effects, or those unable to exercise.