Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Laboratory of Infection and Immunity, Xuzhou Medical University, Xuzhou, 221004, Jiangsu Province, People's Republic of China.
The Second Affiliated Hospital of Nanjing Medical University, Nuclear Medicine Department, Nanjing, 210011, Jiangsu Province, People's Republic of China.
Sci Rep. 2017 Jun 20;7(1):3909. doi: 10.1038/s41598-017-04018-8.
Pathogen-associated biliary fibrosis (PABF) is a type of liver fibrosis characterized by injuries of cholangiocytes and extra cellular matrix (ECM) deposition around bile ducts caused by various bacteria, fungi, virus and parasites. Recent studies show that TLR4 plays an important role in several other types of liver fibrosis, but the mechanism of TLR4 in PABF is yet really unclear. In the present study, a PABF mouse model was established by a trematode infection-Clonorchis sinensis which dwells in the bile ducts and causes severe biliary fibrosis of mice. The results showed that the levels of collagen depositions, α-SMA and hydroxyproline (Hyp) contents in TLR4 mice infected by C. sinensis were significantly lower than in those of TLR4 ones. Furthermore, we found that the activation of TGF-β signaling was impaired in the TLR4 mice, compared with wild mice when they were challenged to the same dose of C. sinensis metacercariae. Moreover, the mice with TLR4 mutation showed a decreased activation of hepatic stellate cells indicated by the expression of α-SMA, when compared with TLR4 mice. These data demonstrate that TLR4 contributes to PABF caused by C. sinensis and TLR4 signaling may be a potential medical target for treatment of PABF.
病原体相关胆管纤维化（PABF）是一种肝纤维化，其特征为各种细菌、真菌、病毒和寄生虫引起的胆管细胞损伤和细胞外基质（ECM）在胆管周围沉积。最近的研究表明，TLR4 在其他几种类型的肝纤维化中发挥着重要作用，但 TLR4 在 PABF 中的作用机制尚不清楚。本研究通过一种寄生于胆管并导致小鼠严重胆管纤维化的吸虫感染建立了 PABF 小鼠模型。结果表明，感染华支睾吸虫的 TLR4 小鼠的胶原沉积、α-SMA 和羟脯氨酸（Hyp）含量明显低于 TLR4 野生型小鼠。此外，与野生型小鼠相比，当给予相同剂量的华支睾吸虫囊蚴时，TLR4 突变小鼠的 TGF-β 信号激活受损。此外，与 TLR4 野生型小鼠相比，TLR4 突变小鼠的肝星状细胞激活减少，表现为 α-SMA 的表达降低。这些数据表明 TLR4 参与了华支睾吸虫引起的 PABF，TLR4 信号可能是治疗 PABF 的潜在医学靶点。
