Loss of SOX18/CLAUDIN5 disrupts the pulmonary endothelial barrier in ventilator-induced lung injury.
Loss of SOX18/CLAUDIN5 disrupts the pulmonary endothelial barrier in ventilator-induced lung injury.
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DOI：
10.3389/fphys.2022.1066515
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发表时间：
2022
影响因子：
4
通讯作者：
中科院分区：
文献类型：
--
作者：
机械应变通过多因素和复杂的机制导致呼吸机诱导的肺损伤（VILI），这些机制尚未得到解决。现有的证据表明，肺内皮细胞紧密连接（TJ）的损失起着至关重要的作用。TJ受生理和血液动力学力的动态调节，以稳定内皮屏障。转录因子性别决定区Y盒（SOX）-18通过其调节内皮TJ蛋白Claudin-5的转录的能力在调节血管发育和血管通透性中是重要的。以前，我们证明了SOX 18的表达增加的剪切应力在肺内皮细胞。因此，在这项研究中，我们研究了通过循环拉伸介导的机械应变如何影响SOX 18/Claudin-5调节轴。我们的数据表明，SOX 18和Claudin-5下调人肺微血管内皮细胞（HLMVEC）暴露于周期性拉伸和小鼠肺暴露于高潮机械通气。SOX 18的过表达减少了周期性牵张HLMVEC中Claudin-5表达的丢失，并保留了内皮屏障功能。此外，在HLMVEC中Claudin-5的过表达改善了暴露于周期性牵张的HLMVEC中的屏障功能障碍，尽管SOX 18表达没有增强。最后，我们发现在肺血管中靶向过表达SOX 18保留了暴露于HIV的小鼠肺中Claudin-5的表达。这反过来又减少了肺血管渗漏，减轻了炎性肺损伤，并保护了肺功能。总之，这些数据表明，增强SOX 18表达可能被证明是治疗呼吸机诱导的肺损伤患者的有用疗法。
Mechanical strain contributes to ventilator-induced lung injury (VILI) through multi-factorial and complex mechanisms that remain unresolved. Prevailing evidence suggests that the loss of pulmonary endothelial tight junctions (TJs) plays a critical role. TJs are dynamically regulated by physiologic and hemodynamic forces to stabilize the endothelial barrier. The transcription factor sex-determining region Y-box (SOX)-18 is important in regulating blood vessel development and vascular permeability through its ability to regulate the transcription of Claudin-5, an endothelial TJ protein. Previously, we demonstrated that SOX18 expression is increased by shear stress in the pulmonary endothelium. Therefore, in this study, we investigated how mechanical strain mediated through cyclic stretch affects the SOX18/Claudin-5 regulatory axis. Our data demonstrate that SOX18 and Claudin-5 are downregulated in human lung microvascular endothelial cells (HLMVEC) exposed to cyclic stretch and the mouse lung exposed to high tidal mechanical ventilation. Overexpression of SOX18 reduced the loss of Claudin-5 expression in HLMVEC with cyclic stretch and preserved endothelial barrier function. Additionally, overexpression of Claudin-5 in HLMVEC ameliorated barrier dysfunction in HLMVEC exposed to cyclic stretch, although SOX18 expression was not enhanced. Finally, we found that the targeted overexpression of SOX18 in the pulmonary vasculature preserved Claudin-5 expression in the lungs of mice exposed to HTV. This, in turn reduced lung vascular leak, attenuated inflammatory lung injury, and preserved lung function. Together, these data suggest that enhancing SOX18 expression may prove a useful therapy to treat patients with ventilator-induced lung injury.
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影响因子：
4.1
作者：
Griffiths, Mark J. D.;McAuley, Danny Francis;Baudouin, Simon V.
通讯作者：
Baudouin, Simon V.
单个基因产物Claudin -1或-2，在成纤维细胞中重构紧密结合的连接链和新兵。
影响因子：
7.8
作者：
Furuse, M;Sasaki, H;Fujimoto, K;Tsukita, S
通讯作者：
Tsukita, S
影响因子：
4
作者：
Catravas, John D.;Snead, Connie;Dimitropoulou, Christiana;Chang, Albert S. Y.;Lucas, Rudolf;Verin, Alexander D.;Black, Stephen M.
通讯作者：
Black, Stephen M.
DOI：
10.1083/jcb.141.7.1539
发表时间：
1998-06-29
期刊：
The Journal of cell biology
影响因子：
--
作者：
Furuse M;Fujita K;Hiiragi T;Fujimoto K;Tsukita S
通讯作者：
Tsukita S
影响因子：
5.6
作者：
Gross, Christine M.;Aggarwal, Saurabh;Kumar, Sanjiv;Tian, Jing;Kasa, Anita;Bogatcheva, Natalia;Datar, Sanjeev A.;Verin, Alexander D.;Fineman, Jeffrey R.;Black, Stephen M.
通讯作者：
Black, Stephen M.