P38/MAPK contributes to endothelial barrier dysfunction via MAP4 phosphorylation-dependent microtubule disassembly in inflammation-induced acute lung injury.
P38/MAPK contributes to endothelial barrier dysfunction via MAP4 phosphorylation-dependent microtubule disassembly in inflammation-induced acute lung injury.
复制标题
在炎症诱导的急性肺损伤中，P38/MAPK 通过 MAP4 磷酸化依赖性微管解体导致内皮屏障功能障碍。
DOI：
10.1038/srep08895
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发表时间：
2015-03-09
影响因子：
4.6
通讯作者：
Huang Y
中科院分区：
文献类型：
--
作者：
Li L;Hu J;He T;Zhang Q;Yang X;Lan X;Zhang D;Mei H;Chen B;Huang Y
炎症过度激活和伴随的肺血管内皮屏障破坏是急性肺损伤（ALI）的主要致病特征。微管相关蛋白4（MAP 4）是一种微管蛋白组装促进蛋白，对维持微管（MT）细胞骨架和细胞-细胞连接结构具有重要作用。然而，MAP 4在ALI中内皮屏障破坏的发展中的参与和确切机制仍然未知。本研究应用脂多糖（LPS）和肿瘤坏死因子-α（TNF-α）刺激体外培养的人肺微血管内皮细胞（HPMECs），以模拟炎症过程中的内皮损伤。我们证明，在LPS和TNF-α刺激HPMECs的同时，MAP 4（Ser 696和Ser 787）磷酸化增加，p38/MAPK通路激活，诱导MT分解，随后通透性增加。此外，紫杉醇的应用、MAP 4（Ala）突变体的过表达或p38/MAPK抑制剂SB 203580的应用抑制了MT破坏和细胞内连接功能障碍。相反，组成性激活p38/MAPK的MKK 6（Glu）导致微管解聚，随后导致高通透性。我们的研究结果揭示了MAP 4在内皮屏障功能障碍中的新作用。
Excessive activation of inflammation and the accompanying lung vascular endothelial barrier disruption are primary pathogenic features of acute lung injury (ALI). Microtubule-associated protein 4 (MAP4), a tubulin assembly-promoting protein, is important for maintaining the microtubule (MT) cytoskeleton and cell-cell junctional structures. However, both the involvement and exact mechanism of MAP4 in the development of endothelial barrier disruption in ALI remains unknown. In this study, lipopolysaccharide (LPS) and tumour necrosis factor-α (TNF-α) were applied to human pulmonary microvascular endothelial cells (HPMECs) to mimic the endothelial damage during inflammation in vitro. We demonstrated that the MAP4 (Ser696 and Ser787) phosphorylation increased concomitantly with the p38/MAPK pathway activation by the LPS and TNF-α stimulation of HPMECs, which induced MT disassembly followed by hyperpermeability. Moreover, the application of taxol, the overexpression of a MAP4 (Ala) mutant, or the application of the p38/MAPK inhibitor SB203580 inhibited the MT disruption and the intracellular junction dysfunction. In contrast, MKK6 (Glu), which constitutively activated p38/MAPK, resulted in microtubule depolymerisation and, subsequently, hyperpermeability. Our findings reveal a novel role of MAP4 in endothelial barrier dysfunction.
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影响因子：
4.8
作者：
Birukova, AA;Birukov, KG;Verin, AD
通讯作者：
Verin, AD
影响因子：
3.1
作者：
Nwariaku, FE;Chang, JP;Turnage, RH
通讯作者：
Turnage, RH
MAP4 磷酸化依赖性线粒体易位是缺氧诱导心肌细胞凋亡的早期步骤。
影响因子：
9
作者：
Hu J;Chu Z;Han J;Zhang Q;Zhang D;Dang Y;Ren J;Chan HC;Zhang J;Huang Y
通讯作者：
Huang Y
影响因子：
5.8
作者：
Lucas, Rudolf;Verin, Alexander D.;Black, Stephen M.;Catravas, John D.
通讯作者：
Catravas, John D.
DOI：
10.1007/978-1-61779-191-8_19
发表时间：
2011-01-01
期刊：
PERMEABILITY BARRIER: METHODS AND PROTOCOLS
影响因子：
--
作者：
Monaghan-Benson, Elizabeth;Wittchen, Erika S.
通讯作者：
Wittchen, Erika S.