Polar head groups are important for barrier-protective effects of oxidized phospholipids on pulmonary endothelium
Polar head groups are important for barrier-protective effects of oxidized phospholipids on pulmonary endothelium
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DOI：
10.1152/ajplung.00395.2006
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发表时间：
2007-04-01
影响因子：
4.9
通讯作者：
Birukov, Konstantin G.
中科院分区：
文献类型：
--
作者：
Birukova, Anna A.;Fu, Panfeng;Birukov, Konstantin G.
我们之前描述了氧化1-棕榈酰-2-花生四烯酰-甘油-3-磷酸胆碱（OxPAPC）对肺内皮细胞（EC）屏障功能的保护作用，并证明了花生四烯酰基部分的环戊烯酮修饰在OxPAPC保护作用中的关键作用。在这项研究中，我们使用氧化磷酸胆碱 (OxPAPC)、磷酸丝氨酸 (OxPAPS) 和甘油磷酸盐 (OxPAPA) 来研究极性头基在 EC 对氧化磷脂 (OxPLs) 屏障保护反应中的作用。 OxPAPC 和 OxPAPS 诱导肺 EC 的持续屏障增强，而根据跨内皮电阻 (TER) 的测量判断，OxPAPA 引起短暂的保护性反应。 Non-OxPLs 对 TER 水平没有影响。所有三种 OxPL 均导致外周 EC 肌动蛋白细胞骨架增强。 OxPAPC 和 OxPAPS 在体外完全消除了 LPS 诱导的 EC 高通透性，而 OxPAPA 仅显示出部分保护作用。在体内，静脉注射 OxPAPS 或 OxPAPC（1.5 mg/kg）显着减弱小鼠气管内 LPS 滴注后支气管肺泡灌洗液中检测到的蛋白质含量、细胞计数和髓过氧化物酶活性的增加，尽管 OxPAPC 显示出较低的效力。所有三种 OxPL 都能部分减弱 IL-6 和凝血酶诱导的 EC 屏障功能障碍。它们对凝血酶诱导的 EC 屏障功能障碍的保护作用与凝血酶诱导的 EC 通透性过高的 Rho 途径的减弱和 Rac 介导的 EC 屏障恢复机制的刺激有关。这些结果首次证明了极性 OxPL 基团在体内外减弱 LPS 诱导的 EC 功能障碍的重要作用，并提出了 OxPL 通过减少 Rho 和刺激 Rac 信号传导来减弱激动剂诱导的通透性过高的机制。
We have previously described protective effects of oxidized 1- palmitoyl- 2- arachidonoylsn- glycero- 3- phosphocholine ( OxPAPC) on pulmonary endothelial cell ( EC) barrier function and demonstrated the critical role of cyclopentenone- containing modifications of arachidonoyl moiety in OxPAPC protective effects. In this study we used oxidized phosphocholine ( OxPAPC), phosphoserine ( OxPAPS), and glycerophosphate ( OxPAPA) to investigate the role of polar head groups in EC barrier-protective responses to oxidized phospholipids ( OxPLs). OxPAPC and OxPAPS induced sustained barrier enhancement in pulmonary EC, whereas OxPAPA caused a transient protective response as judged by measurements of transendothelial electrical resistance ( TER). Non- OxPLs showed no effects on TER levels. All three OxPLs caused enhancement of peripheral EC actin cytoskeleton. OxPAPC and OxPAPS completely abolished LPS-induced EC hyper-permeability in vitro, whereas OxPAPA showed only a partial protective effect. In vivo, intravenous injection of OxPAPS or OxPAPC ( 1.5 mg/ kg) markedly attenuated increases in the protein content, cell counts, and myeloperoxidase activities detected in bronchoalveolar lavage fluid upon intratracheal LPS instillation in mice, although OxPAPC showed less potency. All three OxPLs partially attenuated EC barrier dysfunction induced by IL-6 and thrombin. Their protective effects against thrombin- induced EC barrier dysfunction were linked to the attenuation of the thrombin- induced Rho pathway of EC hyperpermeability and stimulation of Rac- mediated mechanisms of EC barrier recovery. These results demonstrate for the first time the essential role of polar OxPL groups in blunting the LPS- induced EC dysfunction in vitro and in vivo and suggest the mechanism of agonist- induced hyperpermeability attenuation by OxPLs via reduction of Rho and stimulation of Rac signaling.