Anti-inflammatory actions of neuroprotectin D1/protectin D1 and its natural stereoisomers: Assignments of dihydroxy-containing docosatrienes
Anti-inflammatory actions of neuroprotectin D1/protectin D1 and its natural stereoisomers: Assignments of dihydroxy-containing docosatrienes
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DOI：
10.4049/jimmunol.176.3.1848
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发表时间：
2006-02-01
影响因子：
4.4
通讯作者：
Petasis, NA
中科院分区：
文献类型：
--
作者：
Serhan, CN;Gotlinger, K;Petasis, NA
Protectin D1是由神经细胞产生的神经保护素D1，是由二十二碳六烯酸产生的生物活性产物新家族的成员。完整的立体化学的保护素D1（10，17 S-二十二碳三烯），即，手性的碳-10醇和共轭三烯的几何形状，所需的生物活性仍然有待分配。为此，保护素D1/神经保护素D1（PD 1）产生的人类中性粒细胞在小鼠腹膜炎和神经组织中的天然异构体分离，并进行液相色谱-串联质谱和气相色谱-质谱。与通过全有机和生物合成制备的六种10，17-二羟基二十二碳三烯的比较表明，来自人细胞的具有有效生物活性的PD 1是10 R，17 S-二羟基-二十二碳-4Z，7Z，11 E，13 E，15 Z，19 Z-六烯酸。鉴别的其他异构体包括渗出液中存在的痕量Delta 15-trans-PD 1（异构体III）、10 S，17 S-二羟基-二十二碳-4Z，7Z，11 E，13 Z，15 E，19 Z-六烯酸（异构体IV）和双二氧合产物10 S，17 S-二羟基-二十二碳-4Z，7Z，11 E，13 Z，15 E，19 Z-六烯酸（异构体I）。O-18（2）标记显示，10 S，17 S-diHDHA（异构体I）在碳-10位醇中携带O-18，表明连续的脂氧合，而PD 1的形成通过环氧化物进行。PD 1在10 nM时减弱（类似于50%）人中性粒细胞迁移，而Delta 15-trans-PD 1基本上无活性。PDI是腹膜炎中多形核白细胞（PMN）浸润的有效调节剂（在1 ng/小鼠时，与40%相似）。在1- 10-ng剂量下的等级顺序为PD 1接近PD 1甲酯>> Delta 15-trans-PD 1> 10 S，17 S-diHDHA（异构体I）。10 S，17 S-二羟基-二十二碳-4Z，7Z，11 E，13 E，15 Z，19 Z-六烯酸（异构体VI）证实在阻断PMN浸润中>= PD 1，但不是白细胞的主要产物。PD 1也减少了PMN浸润后开始（2小时）的炎症和添加剂与resolvin E1。这些结果表明，PD 1是一种有效的立体选择性抗炎分子。
Protectin D1, neuroprotectin D1 when generated by neural cells, is a member of a new family of bioactive products generated from docosahexaenoic acid. The complete stereochemistry of protectin D1 (10,17S-docosatriene), namely, chirality of the carbon-10 alcohol and geometry of the conjugated triene, required for bioactivity remained to be assigned. To this end, protectin D1/neuroprotectin D1 (PD1) generated by human neutrophils during murine peritonitis and by neural tissues was separated from natural isomers and subjected to liquid chromatography-tandem mass spectrometry and gas chromatography-mass spectrometry. Comparisons with six 10,17-dihydroxydocosatrienes prepared by total organic and biogenic synthesis showed that PD1 from human cells carrying potent bioactivity is 10R,17S-dihydroxy-docosa-4Z,7Z,11E,13E,15Z,19Z-hexaenoic acid. Additional isomers identified included trace amounts of Delta 15-trans-PD1 (isomer III), 10S,17S-dihydroxy-docosa-4Z,7Z,11E,13Z,15E,19Z-hexaenoic acid (isomer IV), and a double dioxygenation product 10S,17S-dihydroxy-docosa-4Z,7Z,11E,13Z,15E,19Z-hexaenoic acid (isomer I), present in exudates. O-18(2) labeling showed that 10S,17S-diHDHA (isomer I) carried O-18 in the carbon-10 position alcohol, indicating sequential lipoxygenation, whereas PD1 formation proceeded via an epoxide. PD1 at 10 nM attenuated (similar to 50%) human neutrophil transmigration, whereas Delta 15-trans-PD1 was essentially inactive. PDI was a potent regulator of polymorphonuclear leukocyte (PMN) infiltration (similar to 40% at 1 ng/mouse) in peritonitis. The rank order at 1- to 10-ng dose was PD1 approximate to PD1 methyl ester >> Delta 15-trans-PD1 > 10S,17S-diHDHA (isomer I). 10S,17S-dihydroxy-docosa-4Z,7Z,11E,13E,15Z,19Z-hexaenoic acid (isomer VI) proved >= PD1 in blocking PMN infiltration, but was not a major product of leukocytes. PD1 also reduced PMN infiltration after initiation (2 h) of inflammation and was additive with resolvin E1. These results indicate that PD1 is a potent stereoselective anti-inflammatory molecule.