Unfractionated heparin ameliorates pulmonary microvascular endothelial barrier dysfunction via microtubule stabilization in acute lung injury.
Unfractionated heparin ameliorates pulmonary microvascular endothelial barrier dysfunction via microtubule stabilization in acute lung injury.
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DOI：
10.1186/s12931-018-0925-6
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发表时间：
2018-11-15
影响因子：
5.8
通讯作者：
Ma X
中科院分区：
文献类型：
--
作者：
Mu S;Liu Y;Jiang J;Ding R;Li X;Li X;Ma X
内皮屏障功能障碍是脓毒症相关性急性肺损伤(ALI)发病机制的核心。血管内皮细胞的微管动力学对内皮屏障功能的调节起着至关重要的作用。普通肝素(UFH)在脓毒症时具有抗炎、保护内皮屏障等多种生物学活性。在此，我们研究了UFH对内毒素(LPS)诱导的内皮屏障功能障碍的影响及其可能机制。将C57BL/6小鼠随机分为载药组、超滤组、脂多糖组和脂多糖 + 超滤组。腹腔注射内毒素30 mg/kg复制脓毒症模型。LPSUFH组小鼠在注射 + 前0.5h静脉注射UFH。培养人肺微血管内皮细胞(HPMECs)，观察UFH对内毒素诱导和诺可达唑诱导的高通透性、F-肌动蛋白重塑和内毒素诱导的p38MAPK激活的影响。UFH可明显减轻内毒素诱导的肺组织病理改变，增加肺W/D比值和伊文思蓝蓄积。体内和体外研究表明，UFH预处理可阻断脂多糖诱导的ALI小鼠模型和人肺微血管内皮细胞(HPMECs)鸟嘌呤核苷酸交换因子(ECFH1)表达和肌球蛋白磷酸酶靶标1亚单位(MYPT1)磷酸化及微管(MT)解体的作用。上述结果提示，UFH通过抑制MT的解离和抑制ECF-H1的表达，改善了脂多糖诱导的内皮屏障功能障碍。此外，UFH还可减轻脂多糖诱导的HPMECs通透性增高和F-肌动蛋白重塑。在体外，UFH预处理可抑制脂多糖诱导的微管蛋白单体表达的增加以及微管蛋白聚合和乙酰化水平的降低。同时，UFH还能改善诺咪唑诱导的MTS解体和内皮屏障功能障碍，并降低p38的磷酸化和活化，这与p38 MAPK抑制剂SB203580的作用相似。UFH通过稳定微管发挥对肺微血管内皮细胞屏障功能障碍的保护作用，并与p38MAPK通路有关。
Endothelial barrier dysfunction is central to the pathogenesis of sepsis-associated acute lung injury (ALI). Microtubule (MT) dynamics in vascular endothelium are crucial for the regulation of endothelial barrier function. Unfractionated heparin (UFH) possesses various biological activities, such as anti-inflammatory activity and endothelial barrier protection during sepsis. Here, we investigated the effects and underlying mechanisms of UFH on lipopolysaccharide (LPS)-induced endothelial barrier dysfunction. C57BL/6 J mice were randomized into vehicle, UFH, LPS and LPS + UFH groups. Intraperitoneal injection of 30 mg/kg LPS was used to induce sepsis. Mice in the LPS + UFH group received intravenous UFH 0.5 h prior to LPS injection. Human pulmonary microvascular endothelial cells (HPMECs) were cultured for analyzing the effects of UFH on LPS-induced and nocodazole-induced hyperpermeability, F-actin remodeling, and LPS-induced p38 MAPK activation. UFH pretreatment significantly attenuated LPS-induced pulmonary histopathological changes, and increased the lung W/D ratio and Evans blue accumulation in vivo. Both in vivo and in vitro studies showed that UFH pretreatment blocked the LPS-induced increase in guanine nucleotide exchange factor (GEF-H1) expression and myosin phosphatase target subunit 1 (MYPT1) phosphorylation, and microtubule (MT) disassembly in LPS-induced ALI mouse model and human pulmonary microvascular endothelial cells (HPMECs). These results suggested that UFH ameliorated LPS-induced endothelial barrier dysfunction by inhibiting MT disassembly and GEF-H1 expression. In addition, UFH attenuated LPS-induced hyperpermeability of HPMECs and F-actin remodeling. In vitro, UFH pretreatment inhibited LPS-induced increase in monomeric tubulin expression and decrease in tubulin polymerization and acetylation. Meanwhile, UFH ameliorates nocodazole-induced MTs disassembly and endothelial barrier dysfunction.Additionally, UFH decreased p38 phosphorylation and activation, which was similar to the effect of the p38 MAPK inhibitor, SB203580. UFH exert its protective effects on pulmonary microvascular endothelial barrier dysfunction via microtubule stabilization and is associated with the p38 MAPK pathway.
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影响因子：
3.2
作者：
Chen, Song;He, Ying;Jin, Guiyun
通讯作者：
Jin, Guiyun
影响因子：
21.3
作者：
Krendel, M;Zenke, FT;Bokoch, GM
通讯作者：
Bokoch, GM
影响因子：
4.8
作者：
Birukova, AA;Birukov, KG;Verin, AD
通讯作者：
Verin, AD
影响因子：
5.6
作者：
Birukova, AA;Birilikov, KG;Verin, AD
通讯作者：
Verin, AD
影响因子：
5.6
作者：
Birukova, AA;Smurova, K;Verin, AD
通讯作者：
Verin, AD