Doxycycline hyclate protects lipopolysaccharide-induced endothelial barrier dysfunction by inhibiting the activation of p38 mitogen-activated protein kinase.
Doxycycline hyclate protects lipopolysaccharide-induced endothelial barrier dysfunction by inhibiting the activation of p38 mitogen-activated protein kinase.
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DOI：
10.1248/bpb.b14-00298
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发表时间：
2014-12
影响因子：
2
通讯作者：
J. Xia;Liqun Wang;Li-li Wu;Qiaobing Huang
中科院分区：
文献类型：
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作者：
J. Xia;Liqun Wang;Li-li Wu;Qiaobing Huang
多西环素盐酸盐(DOX-h)独立于其抗菌作用而减轻炎症状态。本研究旨在观察DOX-h对内毒素(LPS)诱导的内皮屏障功能障碍的影响。用跨内皮细胞电阻(TEER)法检测人脐静脉内皮细胞(HUVECs)的内皮单层通透性。检测丝裂原活化蛋白激酶(MAPKs)的磷酸化和F-肌动蛋白的排列。结果表明，DOX-h预处理和同时处理均可明显减弱内毒素诱导的内皮细胞TEER降低和F-肌动蛋白的解离，并呈剂量和时间依赖关系。脂多糖可介导3种MAPK(p38、细胞外信号调节激酶(ERK)1/2和c-jun氨基末端激酶(JNK))的磷酸化，而DOX-h仅能抑制脂多糖诱导的p38和JNK的磷酸化。这些数据进一步表明DOX-h通过抑制p38及其下游靶标热休克蛋白(HSP)27的磷酸化，减轻了脂多糖诱导的TEER降低和F-肌动蛋白重分布。因此，DOX-h通过抑制p38MAPK-HSP27-F-肌动蛋白通路减轻内毒素诱导的内皮屏障功能障碍。
Doxycycline hyclate (DOX-h) attenuates inflammatory conditions independent of its antimicrobial effect. This study aimed to observe the effects of DOX-h on lipopolysaccharide (LPS)-induced endothelial barrier dysfunction. The endothelial monolayer permeability of human umbilical vein endothelial cells (HUVECs) was monitored by transendothelial electrical resistance (TEER). The phosphorylation of mitogen-activated protein kinases (MAPKs) and the arrangement of F-actin were detected. The results showed that both pretreatment and simultaneous treatment with DOX-h markedly attenuated the LPS-induced reduction in TEER and the disorganization of F-actin on HUVECs in a dose- and time-dependent manner. LPS mediated the phosphorylation of all three MAPKs (p38, extracellular signal-regulated kinase (ERK)1/2, and c-Jun N-terminal kinase (JNK)), but DOX-h was only able to inhibit the LPS-induced phosphorylation of p38 and JNK. The data further suggested that DOX-h alleviated LPS-evoked TEER reduction and F-actin redistribution by inhibiting the phosphorylation of p38 and its downstream target, heat shock protein (HSP)27. Thus, DOX-h attenuates LPS-induced endothelial barrier dysfunction via inhibition of the p38 MAPK-HSP27-F-actin pathway.