Specialized lipid mediators and mechanisms of resolution in vascular injury

描述(由申请人提供)：血管介入治疗失败，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，导致相当大的发病率、死亡率和医疗费用。这些失败最常见的原因是血管管腔变窄(“再狭窄”)，原因是血管壁过度增厚(内膜增生)和瘢痕形成(纤维化)。血管对损伤的反应是由炎症启动并增强的。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，它是由由二十碳五烯酸(EPA)和二十二碳六烯酸(DHA)等多不饱和脂肪酸衍生的特殊的促分解脂质介质介导的。这些介质被称为脂氧素、溶血素、保护素和松脂素，对炎症细胞有很强的作用。 以消除炎症，促进体内平衡的恢复。最近，我们和其他人发现了这些促分解介质在血管细胞上的直接作用，这表明它们可能是血管愈合的重要调节因子，也是血管疾病的候选治疗药物。在这项转化性研究提案中，我们将检验一种假说，即再狭窄是由血管损伤后分辨率的相对缺陷引起的。我们将研究一类重要的促分解脂质介体D系列溶血素对血管平滑肌(VSMC)和外膜细胞的抗炎和细胞抑制作用的分子机制。我们将使用已建立的动物模型来描述在急性动脉损伤中起作用的内源性分解途径，以及通过饮食或局部药物输送干预来操纵这些途径。这些研究将产生新的成果 对血管愈合控制的洞察，并可能导致利用心血管疾病中促分解脂质介体的独特药物生物学的新的治疗方法。

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.