Exercise-enhanced resolution of inflammation

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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.