Exercise-enhanced resolution of inflammation

摘要： 频繁的身体活动可以改善心血管健康和延长寿命，而缺乏身体活动则会使 与过早死亡和全球慢性病负担有关。锻炼的有益效果一直是 在文献中有广泛记载。运动促进骨骼肌生长、心脏肥大和组织 血管生成和改善心血管疾病（CVD）的风险因素谱。尽管如此， 运动不仅仅是降低心血管疾病的危险因素（血压，血脂），涉及的机制和过程， 仍然在很大程度上未知。缺乏对运动有益健康的机制性理解，限制了运动的健康性。 优化健康个体，并阻碍其益处扩展到肥胖和糖尿病个体， 最有可能从运动中获益，不能运动或对其益处无动于衷。一些调查人员 表明心血管疾病危险因素独立的运动效应可能与炎症减少有关。炎症 是一种精心策划的系统反应，旨在降解有害成分，清除组织碎片，促进 愈合和恢复体内平衡。当炎症升级导致炎性细胞侵袭和细胞因子 虽然对炎症的产生进行了广泛的研究，但对炎症是如何解决的却知之甚少。最近的研究工作表明 炎症的消退是由专门的促消退脂质介质（SPM）介导的， 外渗，平息炎症信号，并促进巨噬细胞吞噬作用。SPM是必要且充分的 通过与同源G蛋白偶联受体（GPCR）结合来解决炎症。我们建议， 运动的效果与其通过刺激促炎症消退因子的合成来促进炎症消退的能力有关。 SPM。我们的初步数据表明，运动适应小鼠显示出SPM合成增强，中性粒细胞 清除和增加巨噬细胞吞噬作用，表明运动对解决 炎症我们还发现，儿茶酚胺，这是短暂的运动升高，激活SPM的生物合成 在巨噬细胞中，并增加合成SPM酶5-脂氧合酶（5-LO）和12/15-脂氧合酶（15-LO）。 这些观察结果将运动激活的过程与炎症消退的关键组成部分联系起来， 阐明运动介导的儿茶酚胺产生增加促分解脂质介质的假设 合成并增强炎症的消退。具体目的是：（1）确定运动对 （2）阐明儿茶酚胺在调节运动对解决问题的影响中的作用。 （3）阐明SPM在运动增强消退中的作用。该项目的成果将产生新的 深入了解运动如何调节炎症;哪些过程介导运动的有益效果;以及如何 运动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炎症消退的过程。这些知识可以 导致开发新的治疗干预措施，以增强锻炼的益处或模拟其有益效果 对它的有益效果有抵抗力或不感兴趣的人，或那些不能锻炼的人。

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.