Abstract
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 TLR4mut mice infected by C. sinensis were significantly lower than in those of TLR4wild ones. Furthermore, we found that the activation of TGF-β signaling was impaired in the TLR4mut 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 TLR4wild 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.
Highlights
Infections with pathogens such as bacteria, virus, fungi and parasites can cause biliary fibrosis, which is a chronic liver disease resulted from injuries to cholangiocytes and characterized by accumulation of extra cellular matrix (ECM) around bile ducts[1,2,3,4,5]
To determine whether TLR4 involves in the Pathogen-associated biliary fibrosis (PABF) or not, we developed C. sinensis caused PABF using C3H background mice which could provide us comparable information about the role of TLR4 when compared with C3H/HeJ mice which carries a spontaneous mutation and loss the TLR4 function[27]
We found that TLR4wild mice infected by C. sinensis showed a significant swelling of lobes and massive nodules with different sizes on the surface of lobes, but TLR4mut mice only showed a limited pale area on the surface of lobes
Summary
Infections with pathogens such as bacteria, virus, fungi and parasites can cause biliary fibrosis, which is a chronic liver disease resulted from injuries to cholangiocytes and characterized by accumulation of extra cellular matrix (ECM) around bile ducts[1,2,3,4,5]. Chronic infection with C. sinensis can progress to biliary fibrosis accompanied by the portal/ periportal infiltration of inflammatory cells such as T lymphocyte cells, macrophage cells and neutrophils, and the interaction of these cells may contribute to the process of PABF11, 12. Our previous studies showed that TLR4 was highly expressed in the activated HSC cells and myofibroblasts during C. sinensis-caused biliary fibrosis[11], but the exact role of TLR4 in the pathological process of PABF caused by C. sinensis still remains unknown. The results of the present study will contribute to a better understanding of pathogen-associated biliary fibrogenesis due to the damage of cholangiocytes caused by the pathogen
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