Weng Jie, Zhou Xiaoming, Xie Hui, Gao Ye, Wang Zhiyi, Gong Yuqiang
Department of Emergency Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, China.
Department of Intensive Care Unit, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, China.
Blood Cells Mol Dis. 2019 May;76:7-12. doi: 10.1016/j.bcmd.2018.11.003. Epub 2018 Nov 13.
Transfusion-related acute lung injury (TRALI) remains the leading cause of transfusion-related mortality. Endothelium semipermeable barrier function plays a critical role in the pathophysiology of transfusion-related acute lung injury (TRALI). Recently, Roundabout protein 4 (Robo4), interaction with its ligand Slit 2, was appreciated as a modulator of endothelial permeability and integrity. However, not much is known about the role of Slit2/Robo4 signaling pathway in the pathophysiology of TRALI. In this study, the TRALI model was performed by the "two-event" model of polymorphonuclear neutrophils (PMN)-mediated pulmonary microvascular endothelial cells (PMVECs) damage. We investigated the expression of Slit2/Robo4 and VE-cadherin and examined the pulmonary endothelial hyper-permeability in TRALI model. We found that the expression of Slit2/Robo4 and VE-cadherin were significantly decreased in a time-dependent manner, whereas the PMVECs permeability was gradually increased over time in TRALI model. Moreover, the treatment with Slit2-N, an active fragment of Slit2, increased the expression of Slit2/Robo4 and VE-cadherin to protect PMVECs from PMN-mediated pulmonary endothelial hyper-permeability. These results indicate that targeting Slit2/Robo4 signaling pathway may modulate the permeability as well as protect the integrity of endothelial barrier. In addition, Slit2-N appears to be a promising candidate for developing novel therapies against TRALI.
输血相关急性肺损伤（TRALI）仍然是输血相关死亡的主要原因。内皮半透膜屏障功能在输血相关急性肺损伤（TRALI）的病理生理学中起关键作用。最近，Roundabout蛋白4（Robo4）与其配体Slit 2的相互作用被认为是内皮通透性和完整性的调节因子。然而，关于Slit2/Robo4信号通路在TRALI病理生理学中的作用知之甚少。在本研究中，通过多形核中性粒细胞（PMN）介导的肺微血管内皮细胞（PMVECs）损伤的“双事件”模型建立TRALI模型。我们研究了Slit2/Robo4和血管内皮钙黏蛋白（VE-cadherin）的表达，并检测了TRALI模型中的肺内皮高通透性。我们发现，在TRALI模型中，Slit2/Robo4和VE-cadherin的表达随时间显著降低，而PMVECs的通透性随时间逐渐增加。此外，用Slit2的活性片段Slit2-N处理可增加Slit2/Robo4和VE-cadherin的表达，以保护PMVECs免受PMN介导的肺内皮高通透性的影响。这些结果表明，靶向Slit2/Robo4信号通路可能调节通透性并保护内皮屏障的完整性。此外，Slit2-N似乎是开发抗TRALI新疗法的有希望的候选药物。
