Atherosclerosis: evidence for impairment of resolution of vascular inflammation governed by specific lipid mediators
Atherosclerosis: evidence for impairment of resolution of vascular inflammation governed by specific lipid mediators
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DOI：
10.1096/fj.08-112201
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发表时间：
2008-10-01
期刊：
影响因子：
4.8
通讯作者：
Chan, Lawrence
中科院分区：
文献类型：
--
作者：
Merched, Aksam J.;Ko, Kerry;Chan, Lawrence
动脉粥样硬化是一种累及血管壁的炎症性疾病。最近的研究结果表明，急性炎症并不像以前假设的那样简单地被动解决，而是通过由脂氧合酶启动的特定脂质衍生介质控制的稳态过程主动终止。动物和人类的实验支持5-脂氧合酶系统的促炎作用。相比之下，动物实验的结果显示了动脉粥样硬化中12/15-脂氧合酶途径的一系列反应。迄今为止，仅有的两项临床流行病学人体研究均支持12/15-脂氧合酶下游作用的抗动脉粥样硬化作用。我们通过分析载脂蛋白E缺陷小鼠（1）总体白细胞12/15-脂氧合酶缺陷，2）正常酶表达，或3）巨噬细胞特异性12/15-脂氧合酶过表达，验证了动脉粥样硬化是由于局部炎症消退失败所致的假设。这些结果表明，12/15-脂氧合酶表达通过其在脂质介质（包括脂氧素A（4）、消退素D1和保护素D1）的局部生物合成中的作用保护小鼠免受动脉粥样硬化。这些介质对巨噬细胞和血管内皮细胞发挥有效的激动剂作用，可以控制局部炎症反应的程度。总之，这些研究结果表明，局部内源性解决机制的失败可能是持续炎症的基础，从而助长动脉粥样硬化。
Atherosclerosis is now recognized as an inflammatory disease involving the vascular wall. Recent results indicate that acute inflammation does not simply passively resolve as previously assumed but is actively terminated by a homeostatic process that is governed by specific lipid-derived mediators initiated by lipoxygenases. Experiments with animals and humans support a proinflammatory role for the 5-lipoxygenase system. In contrast, results from animal experiments show a range of responses with the 12/15-lipoxygenase pathways in atherosclerosis. To date, the only two clinical epidemiology human studies both support an antiatherogenic role for 12/15-lipoxygenase downstream actions. We tested the hypothesis that atherosclerosis results from a failure in the resolution of local inflammation by analyzing apolipoprotein E-deficient mice with 1) global leukocyte 12/15-lipoxygenase deficiency, 2) normal enzyme expression, or 3) macrophage-specific 12/15-lipoxygenase overexpression. Results from these indicate that 12/15-lipoxygenase expression protects mice against atherosclerosis via its role in the local biosynthesis of lipid mediators, including lipoxin A(4), resolvin D1, and protectin D1. These mediators exert potent agonist actions on macrophages and vascular endothelial cells that can control the magnitude of the local inflammatory response. Taken together, these findings suggest that a failure of local endogenous resolution mechanisms may underlie the unremitting inflammation that fuels atherosclerosis.