Proresolving actions of a new resolvin D1 analog mimetic qualifies as an immunoresolvent
Proresolving actions of a new resolvin D1 analog mimetic qualifies as an immunoresolvent
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DOI：
10.1152/ajplung.00370.2014
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发表时间：
2015-05-01
影响因子：
4.9
通讯作者：
Serhan, Charles N.
中科院分区：
文献类型：
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作者：
Orr, Sarah K.;Colas, Romain A.;Serhan, Charles N.
炎症的消退是由几个新的内源性脂质介质家族共同创造的专门的促消退介质（SPM）驱动的主动过程。在这里，我们报告了一个合成的类似物resolvin D1（RvD 1）和阿司匹林触发的RvD 1，苯并二炔-17 R-RvD 1-甲酯（BDA-RvD 1），这是使用更少的步骤比所需的天然SPM的全有机合成。BDA-RvD 1对人重组15-前列腺素脱氢酶（RvD 1的主要失活途径）的进一步代谢具有抗性。在缺血-再灌注引发的第二器官损伤中，BDA-RvD 1静脉注射（1 μ g）使中性粒细胞浸润到肺中减少了58 +/- 9%，并且比天然RvD 1显著更有效。100 ng/小鼠的BDA-RvD 1也缩短了大肠埃希菌腹膜炎的消退间隔R-i，其效价与RvD 1相似，从R-i 10.5 h缩短至4.5 h，缩短幅度接近57%。用分离的人吞噬细胞，在皮摩尔浓度（10（-12）M）下的BDA-RvD 1刺激酵母聚糖A颗粒的吞噬作用。BDA-RvD 1以剂量依赖性方式激活人重组G蛋白偶联受体32/DRV 1（RvD 1受体）。这些结果表明，无论是在小鼠体内还是在分离的人细胞中，BDA-RvD 1都具有RvD 1的定义前分解作用，包括抑制白细胞浸润和刺激吞噬作用。此外，它们为一种新的类似物模拟物和免疫溶解剂的实例提供了证据，即一种刺激炎症主动消退的试剂，用于潜在的新治疗类别。
Resolution of inflammation is an active process driven by several new families of endogenous lipid mediators collectively coined specialized proresolving mediators (SPM). Here, we report a synthetic analog of resolvin D1 (RvD1) and aspirin-triggered RvD1, benzo-diacetylenic-17R-RvD1-methyl ester (BDA-RvD1), which was prepared using fewer steps than required for total organic synthesis of natural SPM. BDA-RvD1 was resistant to further metabolism by human recombinant 15-prostaglandin dehydrogenase, a major inactivation pathway for RvD1. In ischemia-reperfusion-initiated second organ injury, BDA-RvD1 intravenously (1 mu g) reduced neutrophil infiltration into the lungs by 58 +/- 9% and was significantly more potent than native RvD1. BDA-RvD1 at 100 ng/mouse also shortened the resolution interval, R-i, of Escherichia coli peritonitis with a similar potency as RvD1, by similar to 57%, from R-i 10.5 h to 4.5 h. With isolated human phagocytes, BDA-RvD1 at picomolar concentrations (10(-12) M) stimulated phagocytosis of zymosan A particles. BDA-RvD1 activated human recombinant G protein-coupled receptor 32/DRV1, an RvD1 receptor, in a dose-dependent manner. These results indicate that, both in vivo in mice and with isolated human cells, BDA-RvD1 shares defining proresolving actions of RvD1, including inhibiting leukocyte infiltration and stimulating phagocytosis. Moreover, they provide evidence for a new analog mimetic and example of an immunoresolvent, namely an agent that stimulates active resolution of inflammation, for a potential new therapeutic class.