Luo Jie, Liang Yuejin, Kong Fanping, Qiu Jingfan, Liu Xinjian, Chen Ailing, Luxon Bruce A, Wu Hannah W, Wang Yong
Department of Pathogen Biology, Key Laboratory of Pathogen Biology of Jiangsu Province, Nanjing Medical University, Nanjing, China.
Comprehensive Laboratory, Ningbo International Travel Healthcare Center, Ningbo, China.
Immunol Cell Biol. 2017 Apr;95(4):399-407. doi: 10.1038/icb.2016.109. Epub 2016 Nov 3.
The activation of hepatic stellate cells (HSCs) is a key event in fibrotic pathogenesis. However, the mechanism involving activation of HSCs in chronic schistosomiasis is not entirely clear. Human HSC LX-2 and human umbilical vein endothelial cells (ECs) were cultured with Schistosoma japonicum antigens (SA) in vitro. Fibrosis-associated genes and cell proliferation were analyzed. HSCs were isolated from mice of chronic schistosomiasis with or without praziquantel (PZQ) treatment, followed by the microarray analysis for the liver fibrosis-associated pathways. Although SA inhibited the activation and proliferation of HSCs, it induced the EC proliferation and vascular endothelial growth factor-a (VEGF) production. VEGF significantly increased the proliferation of HSCs and upregulated the expression of collagen and α-smooth muscle actin. For in vivo study, we found that several fibrosis-associated pathways were involved in the HSCs during the reversal of liver fibrosis caused by schistosomiasis, including VEGF, platelet-derived growth factor, tumor necrosis factor and endothelin-1 pathways. The Ingenuity Pathway Analysis showed that VEGF directly regulated several pro-fibrotic and immune cytokine genes in HSCs, including integrin, fibronectin, interferon-γ, interleukin (IL)-6 and IL-10. Our data indicated the critical role of VEGF signaling in HSC activation in chronic schistosomiasis and highlighted several promising genes and pathways in HSCs as potential targets for therapeutic treatment of liver fibrosis.
肝星状细胞（HSCs）的激活是纤维化发病机制中的关键事件。然而，慢性血吸虫病中涉及HSCs激活的机制尚不完全清楚。将人HSC LX - 2和人脐静脉内皮细胞（ECs）与日本血吸虫抗原（SA）进行体外培养。分析纤维化相关基因和细胞增殖情况。从接受或未接受吡喹酮（PZQ）治疗的慢性血吸虫病小鼠中分离HSCs，随后对肝纤维化相关通路进行微阵列分析。虽然SA抑制了HSCs的激活和增殖，但它诱导了EC增殖和血管内皮生长因子 - a（VEGF）的产生。VEGF显著增加了HSCs的增殖，并上调了胶原蛋白和α - 平滑肌肌动蛋白的表达。对于体内研究，我们发现在血吸虫病引起的肝纤维化逆转过程中，几种纤维化相关通路参与了HSCs的作用，包括VEGF、血小板衍生生长因子、肿瘤坏死因子和内皮素 - 1通路。 Ingenuity通路分析表明，VEGF直接调节HSCs中的几种促纤维化和免疫细胞因子基因，包括整合素、纤连蛋白、干扰素 - γ、白细胞介素（IL） - 6和IL - 10。我们的数据表明VEGF信号在慢性血吸虫病HSC激活中起关键作用，并突出了HSCs中几个有前景的基因和通路作为肝纤维化治疗的潜在靶点。
