Department of Cardiology, Karolinska University Hospital, Stockholm, Sweden.
Columbia University Irving Medical Center, New York, NY, USA.
Nat Rev Cardiol. 2019 Jul;16(7):389-406. doi: 10.1038/s41569-019-0169-2.
Atherosclerosis is a lipid-driven inflammatory disease of the arterial intima in which the balance of pro-inflammatory and inflammation-resolving mechanisms dictates the final clinical outcome. Intimal infiltration and modification of plasma-derived lipoproteins and their uptake mainly by macrophages, with ensuing formation of lipid-filled foam cells, initiate atherosclerotic lesion formation, and deficient efferocytotic removal of apoptotic cells and foam cells sustains lesion progression. Defective efferocytosis, as a sign of inadequate inflammation resolution, leads to accumulation of secondarily necrotic macrophages and foam cells and the formation of an advanced lesion with a necrotic lipid core, indicative of plaque vulnerability. Resolution of inflammation is mediated by specialized pro-resolving lipid mediators derived from omega-3 fatty acids or arachidonic acid and by relevant proteins and signalling gaseous molecules. One of the major effects of inflammation resolution mediators is phenotypic conversion of pro-inflammatory macrophages into macrophages that suppress inflammation and promote healing. In advanced atherosclerotic lesions, the ratio between specialized pro-resolving mediators and pro-inflammatory lipids (in particular leukotrienes) is strikingly low, providing a molecular explanation for the defective inflammation resolution features of these lesions. In this Review, we discuss the mechanisms of the formation of clinically dangerous atherosclerotic lesions and the potential of pro-resolving mediator therapy to inhibit this process.
动脉粥样硬化是一种以动脉内膜为靶器官的脂质驱动的炎症性疾病，其中促炎和抗炎机制的平衡决定了最终的临床结局。内膜浸润和血浆来源的脂蛋白的修饰及其被巨噬细胞摄取，随后形成充满脂质的泡沫细胞，启动动脉粥样硬化病变的形成，而凋亡细胞和泡沫细胞的吞噬作用不足则持续促进病变进展。吞噬作用的缺陷，作为炎症消退不足的标志，导致继发性坏死的巨噬细胞和泡沫细胞的积累，并形成一个具有坏死脂质核心的晚期病变，表明斑块的脆弱性。炎症的消退是由来源于ω-3 脂肪酸或花生四烯酸的专门的促解决脂类介质以及相关蛋白和信号气态分子介导的。炎症消退介质的主要作用之一是将促炎巨噬细胞转化为抑制炎症和促进愈合的巨噬细胞。在晚期动脉粥样硬化病变中，专门的促解决介质与促炎脂质（特别是白三烯）之间的比例明显较低，为这些病变中吞噬作用缺陷的炎症消退特征提供了分子解释。在这篇综述中，我们讨论了临床上危险的动脉粥样硬化病变形成的机制以及促解决介质治疗抑制这一过程的潜力。
