Specialized lipid mediators and mechanisms of resolution in vascular injury

描述（由申请人提供）：血管介入治疗（如血管成形术、支架植入术和旁路手术）失败仍然是一种常见的临床问题，导致相当大的发病率、死亡率和医疗费用。这些失败的最常见原因是由血管壁过度增厚（内膜增生）和瘢痕形成（纤维化）引起的血管腔变窄（“再狭窄”）。血管对损伤的反应是由炎症引发和加强的。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而不是被动的过程，并且是由源自多不饱和脂肪酸（例如二十碳五烯酸（EPA）和二十二碳六烯酸（DHA））的专门促消退脂质介质介导的。这些介质称为脂氧素、消退素、保护素和maresins，它们对炎症细胞发挥有效作用 以消除炎症并促进体内平衡的恢复。最近，我们和其他人已经确定了这些促消退介质对血管细胞的直接作用，这表明它们可能是血管愈合的重要调节剂，以及血管疾病的候选治疗剂。在这项转化研究提案中，我们将检验再狭窄是由血管损伤后的分辨率相对不足引起的假设。我们将研究的分子机制，其中一类重要的前解决脂质介质，D-系列resolvins，发挥抗炎和细胞生长抑制作用的血管平滑肌（VSMC）和外膜细胞。我们将使用已建立的动物模型描述在急性动脉损伤的情况下可操作的内源性分辨率途径，以及通过饮食或局部药物递送干预对其进行操纵。这些研究将产生新的 这可能有助于深入了解血管愈合的控制，并可能导致利用心血管疾病中促消退脂质介质的独特药理学的新治疗方法。

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.