Specialized lipid mediators and mechanisms of resolution in vascular injury

描述（由申请人提供）：血管干预失败，如血管成形术、支架植入和搭桥手术仍然是一个常见的临床问题，导致相当高的发病率、死亡率和医疗保健支出。这些失败最常见的原因是由于血管壁过度增厚（内膜增生）和瘢痕（纤维化）引起的血管管腔狭窄（再狭窄）。血管对损伤的反应是由炎症引发和增强的。这种反应的大小，包括其时间和空间范围，是血管重塑结果的主要决定因素。最近的研究表明，炎症的消退是一个主动的过程，而不是一个被动的过程，并且是由来自多不饱和脂肪酸的专门的促溶解脂质介质介导的，如二十碳五烯酸（EPA）和二十二碳六烯酸（DHA）。这些介质-被称为脂毒素，溶解蛋白，保护蛋白和蛋白-对炎症细胞发挥强大的作用

DESCRIPTION (provided by applicant): Failure of vascular interventions such as angioplasty, stenting, and bypass surgery remains a common clinical problem resulting in considerable morbidity, mortality, and healthcare expenditures. The most common cause of these failures is a narrowing of the vessel lumen ("restenosis") resulting from excessive thickening of the vessel wall (intimal hyperplasia) and scarring (fibrosis). The response of blood vessels to injury is initiated and potentiated by inflammation. The magnitude of this response, including its temporal and spatial extent, is a primary determinant of the vessel remodeling outcome. Recent studies have suggested that the resolution of inflammation is an active, rather than a passive process, and is mediated by specialized pro-resolving lipid mediators derived from polyunsaturated fatty acids such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). These mediators - termed lipoxins, resolvins, protectins, and maresins - exert potent effects on inflammatory cells to turn off inflammation and promote a return of homeostasis. Recently we and others have identified direct actions of these pro-resolving mediators on vascular cells which suggest they may be important modulators of vascular healing, and candidate therapeutics for vascular disease. In this translational research proposal, we will examine the hypothesis that restenosis is caused by a relative deficit in resolution following vascular injury. We will examine the molecular mechanisms by which one important class of pro-resolving lipid mediators, the D-series resolvins, exerts anti-inflammatory and cytostatic effects on vascular smooth muscle (VSMC) and adventitial cells. We will characterize the endogenous resolution pathways that are operative in the setting of acute arterial injury using an established animal model, and their manipulation by either dietary or local drug delivery interventions. These studies will yield novel insights into the control of vascular healing, and may lead to new therapeutic approaches leveraging the unique pharmacobiology of pro-resolving lipid mediators in cardiovascular diseases.