Janus-kinase-2 relates directly to portal hypertension and to complications in rodent and human cirrhosis
Janus-kinase-2 relates directly to portal hypertension and to complications in rodent and human cirrhosis
复制标题
DOI：
10.1136/gutjnl-2015-309600
复制
发表时间：
2017-01-01
期刊：
影响因子：
24.5
通讯作者：
Trebicka, Jonel
中科院分区：
文献类型：
--
作者：
Klein, Sabine;Rick, Johanna;Trebicka, Jonel
目的血管紧张素II（AngII）通过血管紧张素II I型受体（AT 1 R）Janus激酶2（JAK 2）/Arhgef 1途径激活，继而激活RHOA/Rhokinase（ROCK），诱导实验性肝纤维化。本研究探讨了JAK 2实验和人类门脉高压症的关系。设计JAK 2/ARHGEF 1信号传导成分的mRNA和蛋白水平进行了分析，在49人的肝脏样本和相关的门脉高压症的临床参数，在这些患者。相应地，肝纤维化（胆管结扎（BDL），四氯化碳（CCl 4））诱导在SM 22启动子（SM 22（Cre+）-Jak 2（f/f））的ped-Jak 2基因敲除小鼠。分析了来自健康和纤维化小鼠和大鼠的原代肌成纤维细胞的转录和收缩。在两种不同的肝硬化模型中结果JAK 2/ARHGEF 1通路各组分在肝硬化中的转录水平上调，并与肝硬化的病因、严重程度和并发症有关（终末期肝病模型（MELD）评分、Child评分以及腹水、高危静脉曲张、自发性细菌性腹膜炎）。在纤维化诱导后，缺乏Jak 2的SM 22（Cre+）-Jak 2f/f小鼠比SM 22（Cre-）-Jak 2（f/f）发生更少的纤维化和更低的门静脉压力（PP）。来自SM 22（Cre+）-Jak 2（f/f）小鼠的肌成纤维细胞在激活后表达较少的胶原蛋白和促纤维化标记物。AG 490在体外松弛活化的肝星状细胞。AG 490可降低肝硬化大鼠的肝血管阻力，从而降低PP。结论肝组织JAK 2/ARHGEF 1/ROCK的表达与肝硬化门脉高压和失代偿有关。肌成纤维细胞中Jak 2的缺失减轻了实验性纤维化，并且JAK 2的急性抑制降低了PP。因此，JAK 2抑制剂，已经在临床上用于其他适应症，可能是一种新的方法来治疗肝硬化门静脉高压症。
Objective Angiotensin II (AngII) activates via angiotensin-II-type-I receptor (AT1R) Janus-kinase-2 (JAK2)/Arhgef1 pathway and subsequently RHOA/Rhokinase (ROCK), which induces experimental and probably human liver fibrosis. This study investigated the relationship of JAK2 to experimental and human portal hypertension.Design The mRNA and protein levels of JAK2/ARHGEF1 signalling components were analysed in 49 human liver samples and correlated with clinical parameters of portal hypertension in these patients. Correspondingly, liver fibrosis (bile duct ligation (BDL), carbon tetrachloride (CCl4)) was induced in floxed-Jak2 knock-out mice with SM22-promotor (SM22(Cre+)-Jak2(f/f)). Transcription and contraction of primary myofibroblasts from healthy and fibrotic mice and rats were analysed. In two different cirrhosis models (BDL, CCl4) in rats, the acute haemodynamic effect of the JAK2 inhibitor AG490 was assessed using microsphere technique and isolated liver perfusion experiments.Results Hepatic transcription of JAK2/ARHGEF1 pathway components was upregulated in liver cirrhosis dependent on aetiology, severity and complications of human liver cirrhosis (Model for End-stage Liver disease (MELD) score, Child score as well as ascites, high-risk varices, spontaneous bacterial peritonitis). SM22(Cre+)-Jak2f/f mice lacking Jak2 developed less fibrosis and lower portal pressure (PP) than SM22(Cre-)-Jak2(f/f) upon fibrosis induction. Myofibroblasts from SM22(Cre+)-Jak2(f/f) mice expressed less collagen and profibrotic markers upon activation. AG490 relaxed activated hepatic stellate cells in vitro. In cirrhotic rats, AG490 decreased hepatic vascular resistance and consequently the PP in vivo and in situ.Conclusions Hepatic JAK2/ARHGEF1/ROCK expression is associated with portal hypertension and decompensation in human cirrhosis. The deletion of Jak2 in myofibroblasts attenuated experimental fibrosis and acute inhibition of JAK2 decreased PP. Thus, JAK2 inhibitors, already in clinical use for other indications, might be a new approach to treat cirrhosis with portal hypertension.