Wang Dong, Yin Jikai, Dong Rui, Zhao Jian, Wang Qing, Wang Nan, Wang Shouli, Du Xilin, Lu Jianguo
Department of General Surgery, TangDu Hospital, Fourth Military Medical University, Xi'an, China.
Department of Orthopedics, TangDu Hospital, Fourth Military Medical University, Xi'an, China.
Dig Liver Dis. 2015 Apr;47(4):315-23. doi: 10.1016/j.dld.2014.12.017. Epub 2015 Jan 12.
JAK2/STAT3 signalling promotes fibrosis, angiogenesis and inflammation in many diseases; however, the role of this pathway in portal hypertension remains obscure. This study aimed to explore the function of JAK2/STAT3 signalling in portal hypertension and estimate the potential therapeutic effect of treatment with the specific inhibitor AG490.
Rats induced by partial portal vein ligation and common bile duct ligation were treated with AG490 for two weeks. Haemodynamic parameters were assessed. The levels of phospho-STAT3 protein and related cytokines were detected by western blotting of splanchnic organs. Liver, spleen and intestine characterization was performed using histological analyses. Peripheral blood cell counts were also detected.
High levels of phospho-STAT3 protein were detected in portal hypertensive rats. AG490 effectively inhibited JAK2/STAT3 signalling and its downstream cytokines and provided protective effects by decreasing splanchnic neovascularization and inflammation and by attenuating portal pressure and hyperdynamic splanchnic circulation. In cirrhosis rats, AG490 inhibited intrahepatic fibrosis, angiogenesis and inflammation. AG490 improved the peripheral blood cell counts and the splenomegaly observed in these rats.
JAK2/STAT3 signalling is essential in portal hypertension, and targeting JAK2/STAT3 may be a promising therapy to treat this condition.
JAK2/STAT3信号通路在多种疾病中促进纤维化、血管生成和炎症反应；然而，该通路在门静脉高压中的作用仍不清楚。本研究旨在探讨JAK2/STAT3信号通路在门静脉高压中的功能，并评估特异性抑制剂AG490治疗的潜在疗效。
对部分门静脉结扎和胆总管结扎诱导的大鼠用AG490治疗两周。评估血流动力学参数。通过对内脏器官进行蛋白质免疫印迹法检测磷酸化STAT3蛋白和相关细胞因子的水平。采用组织学分析对肝脏、脾脏和肠道进行特征描述。还检测外周血细胞计数。
在门静脉高压大鼠中检测到高水平的磷酸化STAT3蛋白。AG490有效抑制JAK2/STAT3信号通路及其下游细胞因子，并通过减少内脏新生血管形成和炎症反应、减轻门静脉压力和内脏高动力循环发挥保护作用。在肝硬化大鼠中，AG490抑制肝内纤维化、血管生成和炎症反应。AG490改善了这些大鼠的外周血细胞计数和脾肿大。
JAK2/STAT3信号通路在门静脉高压中至关重要，靶向JAK2/STAT3可能是治疗这种疾病的一种有前景的疗法。
