Institute of Immunology, Third Military Medical University (Military Medical University of the Army), PLA, Chongqing, 400038, People's Republic of China.
Embryology, Nanjing Medical University, Nanjing, Jiangsu, 210029, People's Republic of China.
Immunol Res. 2017 Oct;65(5):1046-1058. doi: 10.1007/s12026-017-8946-7.
The blood glycoprotein von Willebrand factor (vWF) is involved in coagulopathy and inflammation; however, its role in the pathogenesis of acute liver failure, as suggested by its higher expression levels in such patients, remains unknown. In this study, vWF-knockout (KO) mice showed more severe carbon tetrachloride (CCl)-induced liver injury than wild-type mice. Patients with acute liver injury also showed elevated vWF protein activity and expression in liver tissues, as compared to healthy individuals. Using the mouse model and cultured human umbilical vein endothelial cells (HUVECs), CCl was found to directly increase vWF protein expression through interaction with the highly expressed vWF receptor, GPIbα. Microarray analysis revealed that the genes showing the most differential expression in response to CCl-induced liver injury and vWF deficiency were related to the MAPK signaling pathway. Subsequent inhibition of vWF protein activity in HUVECs led to activation of the MAPK signal pathway and elevated production of FGL2, and treatment with a phospho-p38 inhibitor suppressed the CCl-induced production of FGL2. Exposure of liver sinusoidal endothelial cells isolated from the vWF-KO acute liver injury model mice to phospho-p38 inhibitor also decreased FGL2 expression. The vWF/GPIbα axis plays a protective role against development of acute liver injury by attenuating FGL2 production through the MAPK signaling pathway. Collectively, these data provide insight into the pathogenesis of acute liver injury and a potential novel strategy for its treatment.
血液糖蛋白血管性血友病因子（vWF）参与凝血异常和炎症；然而，正如其在这些患者中表达水平升高所表明的那样，其在急性肝衰竭发病机制中的作用尚不清楚。在这项研究中，vWF 敲除（KO）小鼠比野生型小鼠表现出更严重的四氯化碳（CCl）诱导的肝损伤。与健康个体相比，急性肝损伤患者的肝组织中也表现出升高的 vWF 蛋白活性和表达。使用小鼠模型和培养的人脐静脉内皮细胞（HUVEC），发现 CCl 通过与高表达的 vWF 受体 GPIbα相互作用直接增加 vWF 蛋白表达。微阵列分析显示，对 CCl 诱导的肝损伤和 vWF 缺乏反应的基因显示出最显著差异的基因与 MAPK 信号通路有关。随后抑制 HUVEC 中的 vWF 蛋白活性导致 MAPK 信号通路的激活和 FGL2 的产生增加，并且用磷酸化 p38 抑制剂处理可抑制 CCl 诱导的 FGL2 的产生。将来自 vWF-KO 急性肝损伤模型小鼠的肝窦内皮细胞暴露于磷酸化 p38 抑制剂也降低了 FGL2 的表达。vWF/GPIbα 轴通过 MAPK 信号通路减弱 FGL2 的产生发挥保护作用，从而减轻急性肝损伤的发展。总之，这些数据提供了对急性肝损伤发病机制的深入了解，并为其治疗提供了一种潜在的新策略。
