syndecan4对机械通气肺损伤的作用及机制研究

The increase of pulmonary endothelial permeability is a central part of ventilator-induced lung injury （VILI). Small GTPases act as molecular switch, and the most extensively characterized members are RhoA, Rac1, which have distinct effects on actin cytoskeleton and endothelial barrier. Syndecan-4 is a transmembrane proteoglycan ,which dynamic adjusting the activation of the Small GTPases by PKCa.It has been verified that syndecan-4 is an important mechanosensing molecule.However, to date, the effect of syndecan4 in VILI is unknown .In our preliminary experiment , a significant increase of syndecan4 was found in the high volume mechanical ventilation when compared to the control group , and also was in accordance with the extent of the lung injury , which further verificated that syndecan4 was sensitive to mechanical stretch, and it may participate in VILI . Thus we presume that syndecan4 may regulate Rho/ROCK signal mechanism and participate in VILI. Our research group would establish the model of ventilator induced lung injury in rat and the model of pulmonary endothelial cycle stretch, use the technology of gene interference and so on, to explore the role of syndecan4 in VILI and the molecular mechanism, with a view to provide new ideas for clinical prevention of VILI.

肺血管内皮细胞通透性增加是机械通气肺损伤（VILI）发生的中心环节。小G蛋白Rho超家族（包括RhoA、Rac1等），在细胞的信号传导中作为分子开关，动态调控细胞骨架及内膜屏障的变化。syndecan4是一种跨膜蛋白聚糖，通过PKCa，动态调节小G蛋白活性。近期研究证实syndecan4是一种重要的机械牵张敏感蛋白，但关于syndecan4在过度机械牵张致肺损伤中的作用，目前尚无系统研究。预实验发现大鼠大潮气量机械通气组肺组织中Syndecan4表达较对照组提高，与肺损伤程度一致，进一步佐证了syndecan4对机械牵张较为敏感，可能参与VILI的发生。据此推测syndecan4可能通过调控Rho/ROCK信号途径来参与VILI的发生。本课题组建立整体VILI及肺血管内皮细胞机械牵张模型，应用基因干扰等技术，探讨syndecan4在调控VILI中的作用及机制，为临床VILI的防治提供新思路

肺血管内皮细胞通透性增加是机械通气肺损伤（VILI）发生的中心环节。小G蛋白Rho超家族（包括RhoA、Rac1等），在细胞的信号传导中作为分子开关，动态调控细胞骨架及内膜屏障的变化。syndecan4是一种跨膜蛋白聚糖，其可通过PKCa，动态调节小G蛋白活性。我们提出： syndecan4作为一种重要的机械牵张敏感蛋白，可能通过调控Rho/ROCK信号途径,参与调节VILI的发生。本研究通过建立整体VILI及肺血管内皮细胞机械牵张模型，探讨syndecan4在调控VILI中的作用及机制。主要研究显示：（1）实验显示syndecan4对过度牵张所致肺血管内皮细胞损伤有一定的保护作用，表现为syndecan基因的缺失导致肺血管内皮细胞凋亡和细胞骨架的破坏进一步加重，炎性反应进一步加重；（2）Syndecan4蛋白通过抑制RhoA,调节Rho/ROCK/ERM信号途径，减轻肺血管内皮细胞凋亡及细胞骨架的改变，发挥对过度牵张所致肺损伤的保护作用。所获研究成果将进一步加深人们对VILI 发病机制的认识，为临床防治VILI 进一步提供实验依据，同时为临床治疗或药物干预VILI 提供合适的靶分子，具有重大的研究价值。