Dual inhibition of reactive oxygen species and spleen tyrosine kinase as a therapeutic strategy in liver fibrosis
Dual inhibition of reactive oxygen species and spleen tyrosine kinase as a therapeutic strategy in liver fibrosis
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活性氧和脾酪氨酸激酶的双重抑制作为肝纤维化的治疗策略
DOI：
10.1016/j.freeradbiomed.2021.08.241
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发表时间：
2021-09-08
影响因子：
7.4
通讯作者：
Zhu, Kangshun
中科院分区：
文献类型：
--
作者：
Hu, Qiaoting;Liu, Mingyu;Zhu, Kangshun
肝星状细胞（hepatic stellate cells，HSC）在肝纤维化（liver fibrosis，LF）和肝细胞癌（hepatocellular carcinoma，HCC）的发生发展中起着重要作用。我们以前报道过脾酪氨酸激酶（SYK）是HSC活化的关键，然而，其机制还不完全清楚。在本研究中，我们发现SYK通过促进活性氧（ROS）的产生，促进自噬以促进HSC活化。然而，SYK抑制剂GS-9973可以有效地减少体外HSC的ROS生成，但在体内没有。从机制上讲，肝细胞（HC）会在体外释放ROS，然后扩散到HSC中，以促进炎症背景下的自噬和激活。然后，我们进一步检查了用或不用不同剂量的水飞蓟宾（一种天然化合物，其特征在于具有良好的抗氧化和保肝特性）处理的四氯化碳（CCl 4）诱导的小鼠的肝切片和原代肝细胞中的ROS含量，发现肝切片和其剥夺的原代细胞中的ROS强度以剂量依赖性方式被有效地抑制。最后，我们评估了水飞蓟宾和GS-9973在治疗CCl 4诱导的小鼠中的合理组合，发现该组合耐受性良好，并且对HSC活性、LF和HCC具有协同作用。水飞蓟宾和GS-9973的联合使用可能是患有LF甚至HCC的患者的有希望的治疗策略。
Hepatic stellate cells (HSCs) play key roles in liver fibrosis (LF) and hepatocellular carcinoma (HCC). We previously reported that spleen tyrosine kinase (SYK) is critical for HSCs activation, however, the mechanisms are insufficiently understood. In the present study, we found that SYK facilitated autophagy to promote HSCs activation by enhancing reactive oxygen species (ROS) generation. However, SYK inhibitor GS-9973 could efficiently reduce HSCs ROS generation in vitro but not in vivo. Mechanistically, hepatocytes (HCs) would release ROS outside and then diffuse into HSCs to promote autophagy and activation in vitro in the context of inflammation. We then further examined the ROS contents in liver sections and primary liver cells of carbon tetrachloride (CCl4) induced mice treated with or without different doses of Silybin, a natural compound characterized by a well-established antioxidant and hepatoprotective properties, and found that ROS intensities in both liver sections and their deprived primary cells were efficiently inhibited in a dose-dependent fashion. Lastly, we evaluated the rational combination of Silybin and GS-9973 in the treatment of CCl4 induced mice and found that this combination is well tolerated and acts synergistically against HSCs activity, LF and HCC. The combinational use of Silybin and GS-9973 could be a promising therapeutic strategy in patients suffering from LF and even HCC.