肝脏祖细胞IL-13/IL-13Rα2/Activin A/CTGF 轴促进日本血吸虫病肝纤维化的作用和机制研究

Hepatic progenitor cells involve various kinds of liver fibrosis. However, little is known about their role in liver fibrosis induced Shistosome japonicum. Our previous work shows hepatic progenitor cells are activated and expanded in the human and mouse fibrotic liver tissues induced by Schistosome japonicum. Studies reveal that IL-13/IL-13Rα2 mediates connective tissue growth factor (CTGF) expression by ALK/Smad signaling pathway. IL-13 is able to induce the production of Activin A. Our previous report illuminates that Activin A mediates CTGF expression in hepatic progenitor cells through ALK4/Smad signaling pathway. Besides, we find that human Schistosome japonicum-induced fibrotic liver tissues show higher IL-13 and IL-13Rα2 expression than normal liver tissue. Moreover, IL-13Rα2 expression is detected in hepatic progenitor cell lines LE/6 and WB-F344. Thus, we propose that IL-13/IL-13Rα2/Activin A/CTGF axis in hepatic progenitor cells promotes liver fibrosis induced by Shistosome japonicum. This project will clarify the role of hepatic progenitor cells in the process of liver fibrosis induced Shistosome japonicum and their possible molecular mechanism through in vivo and in vitro experiments as well as detection on clinical specimens, which will offer new theory and therapy target to comprehensive and targeted treatment of liver fibrosis caused Schistosome japonicum.

肝脏祖细胞参与多种纤维化疾病，然而，其在日本血吸虫病肝纤维化中的作用及机制目前尚不明了。我们前期工作发现在人体和小鼠日本血吸虫病肝纤维化组织中肝脏祖细胞存在激活和扩增。文献报道IL-13/IL-13Rα2依赖ALK/Smad介导CTGF表达；IL-13促进Activin A分泌。我们的文章报道Activin A激活ALK4/Smad通路上调肝脏祖细胞表达CTGF。我们的预实验发现人体日本血吸虫病肝纤维化组织表达IL-13及IL-13Rα2，肝脏祖细胞系LE/6和WB-F344表达IL-13Rα2。据此推测肝脏祖细胞IL-13/IL-13Rα2/Activin A/CTGF轴促进日本血吸虫病肝纤维化。本项目将从体内、体外和临床样本三个水平验证肝脏祖细胞在日本血吸虫病肝纤维化中的作用及其可能的分子机制，为日本血吸虫病肝纤维化的靶向综合治疗提供新的理论依据和新的治疗靶点。

本项目旨在研究肝脏祖细胞是否参与日本血吸虫性肝纤维化及IL-13/IL-13Rα2信号轴促进血吸虫肝纤维化的相关机制。如期完成本项目研究。. 本项目的主要研究内容是证实肝脏祖细胞参与日本血吸虫病肝纤维化，并明确IL-13/IL-13Rα2参与了血吸虫性肝纤维化，其与纤维化程度的相关性。IL-13/IL-13Rα2通过激活ALK4/Smad通路，促进日本血吸虫病肝纤维化。然后进一步研究其激活下游通路的相关分子机制。. 目前已取得如下研究成果：.1）肝脏祖细胞参与血吸虫性肝纤维化,并与纤维化程度相关。.2）IL-13/IL-13Rα2通路参与了血吸虫性肝纤维化。.3）IL-13/IL-13Rα2通过激活ALK4/Smad通路，促进日本血吸虫病肝纤维化.4）IL-13/IL-13Rα2能够激活下游分子通路，从而激活ALK4/Smad通路，促进日本血吸虫病肝纤维化。. 本研究揭示了肝脏祖细胞在血吸虫性肝纤维化中发挥重要中，同时进一步明确IL-13受体IL-13Rα2并非“诱饵受体”，而是能够激活下游特异性的信号通路来促进血吸虫性肝纤维化，丰富血吸虫性肝纤维化的理论体系，也为日本血吸虫病肝纤维化靶向综合治疗提供新的思路。.