MAP kinases in lung endothelial permeability induced by microtubule disassembly
MAP kinases in lung endothelial permeability induced by microtubule disassembly
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DOI：
10.1152/ajplung.00447.2004
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发表时间：
2005-07-01
影响因子：
4.9
通讯作者：
Verin, AD
中科院分区：
文献类型：
--
作者：
Birukova, AA;Birukov, KG;Verin, AD
Anna A. Birukova, Konstantin G. Birukov, Boris Gorshkov, Liu Feng, Joe G. N. Garcia和Alexander D. Verin。MAP激酶在微管解体诱导的肺内皮通透性中的作用。[J] .中国生物医学工程学报，2016,31(2):559 - 564。2005年3月18日首次出版；doi: 10.1152 / ajplung.00447.2004。肺内皮屏障功能受多种信号通路调控，包括丝裂原活化蛋白激酶（MAPK）、细胞外信号调节激酶（ERK） 1/2和p38。我们最近显示了微管（MT）解体参与内皮细胞（EC）屏障失效。在这项研究中，我们研究了ERK1/2和p38 MAPK在肺内皮细胞屏障功能障碍中与MT解体相关的潜在参与。MT抑制剂nocodazole （0.2 μ M）和vinblastine （0.1 μ M）诱导Ras-Raf-MEK1/2-ERK1/2和MKK3/6-p38-MAPKAPK2在人和牛肺EC中持续激活MAPK级联反应，通过磷酸化特异性抗体和MAPK激活试验检测。这些影响与渗透性增加有关，通过测量跨内皮电阻和细胞骨架重塑来分析EC单层的形态。紫杉醇稳定MT （5 μ M, 1 h）减弱nocodazoll诱导的ERK1/2和p38 MAPK活化，磷酸化p38 MAPK底物27-kDa热休克蛋白和调节肌球蛋白轻链，这些蛋白参与肌动蛋白聚合和肌动球蛋白收缩。重要的是，SB-203580 （20 μ M， 1小时）仅对p38 MAPK进行药理学抑制，可减轻诺可达唑诱导的MT解聚、肌动蛋白重塑和EC屏障功能障碍，而MEK/ERK1/2抑制剂U0126 （5 μ M， 1小时）没有效果。这些数据表明p38 MAPK激活、MT网络重塑和EC屏障调节之间存在直接联系。
Birukova, Anna A., Konstantin G. Birukov, Boris Gorshkov, Feng Liu, Joe G. N. Garcia, and Alexander D. Verin. MAP kinases in lung endothelial permeability induced by microtubule disassembly. Am J Physiol Lung Cell Mol Physiol 289: L75-L84, 2005. First published March 18, 2005; doi:10.1152/ajplung.00447.2004.-Lung endothelial barrier function is regulated by multiple signaling pathways, including mitogen-activated protein kinases (MAPK) extracellular signal-regulated kinases (ERK) 1/2 and p38. We have recently shown involvement of microtubule (MT) disassembly in endothelial cell (EC) barrier failure. In this study, we examined potential involvement of ERK1/2 and p38 MAPK in lung EC barrier dysfunction associated with MT disassembly. MT inhibitors nocodazole (0.2 mu M) and vinblastine (0.1 mu M) induced sustained activation of Ras-Raf-MEK1/2-ERK1/2 and MKK3/6-p38-MAPKAPK2 MAPK cascades in human and bovine pulmonary EC, as detected by phosphospecific antibodies and in MAPK activation assays. These effects were linked to increased permeability assessed by measurements of transendothelial electrical resistance and cytoskeletal remodeling analyzed by morphometric analysis of EC monolayers. MT stabilization by taxol (5 mu M, 1 h) attenuated nocodazole-induced ERK1/2 and p38 MAPK activation and phosphorylation of p38 MAPK substrate 27-kDa heat shock protein and regulatory myosin light chains, the proteins involved in actin polymerization and actomyosin contraction. Importantly, only pharmacological inhibition of p38 MAPK by SB-203580 (20 mu M, 1 h) attenuated nocodazole-induced MT depolymerization, actin remodeling, and EC barrier dysfunction, whereas the MEK/ERK1/2 inhibitor U0126 (5 mu M, 1 h) exhibited no effect. These data suggest a direct link between p38 MAPK activation, remodeling of MT network, and EC barrier regulation.