Toll样受体4在胆道损伤修复过程中的表达及意义

目的:探讨Toll样受体4(TLR4)在胆道损伤修复过程中的作用。方法:用免疫组化检测12例良性胆道狭窄胆管组织与4例正常胆管组织中TLR4的表达。用钳夹法在TLR4基因缺陷(TLR4~(-/-))小鼠和野生(TLR4~(+/+))小鼠上建立胆道损伤修复模型,并设各自的假手术对照,术后48h观察各组肝脏及胆管组织病理学变化及肝功能情况。结果:TLR4主要表达于胆管内皮细胞,良性胆道狭窄胆管壁表达阳性率明显高于正常胆管组织(83.33%vs.25.00%,P0.01)。两个假手术组小鼠术后肝脏及胆管组织均未见病理改变,TLR4~(-/-)与TLR4~(+/+)模型组小鼠均出现明显的胆道及肝脏损伤,但前者较后者明显减轻;与各自的对照组比较,TLR4~(-/-)与TLR4~(+/+)模型组小鼠血清谷丙转氨酶、总胆红素、直接胆红素水平均明显升高(均P0.05),但前者各项指标的升高程度均明显低于后者(均P0.05)。结论:TLR4可能通过参与胆管上皮细胞的天然免疫应答,并启动一系列炎症因子的表达,促使成纤维细胞增殖,在胆管良性狭窄中起到重要作用。

Toll-like receptor 4 expression in the repairing process of bile duct injury and its significance

Objective: To investigate the role of Toll-like receptor 4 (TLR4) in the repairing process of bile duct injury. Methods: The TLR4 expressions in 12 specimens of bile duct tissue with biliary stricture and 4 specimens of normal bile duct tissue were determined by immunohistochemical staining. Biliary injury and repair model was established in TLR4 deficient (TLR4–/–) and wild-type (TLR4+/+) mice using clamping method, with their corresponding sham-operated mice as control, and the pathological changes and liver function status were observed in each group of mice 48 h after operation. Results: TLR4 was expressed mainly in the endothelial cells of the bile ducts, and its positive expression rate in bile duct wall with benign biliary stricture was significantly higher than that in bile duct wall of normal tissue (83.33% vs. 25.00%, P<0.01). No pathological changes were noted in the liver and bile duct tissues in the two groups of sham-operated mice, while obvious liver and bile duct injuries were seen in model groups of both TLR4–/– and TLR4+/+ mice, but the injuries were markedly milder in the former than those in the latter; compared with corresponding sham-operated control, the serum levels of alanine transaminase, and total or direct bilirubin in model groups of both TLR4–/– and TLR4+/+ mice were significantly increased (all P<0.05), but the increasing amplitudes of these parameters in the former were significantly slighter than those in the latter (all P<0.05). Conclusion: TLR4 contributes critically to benign bile duct stricture probably via participating in the natural immune responses of biliary epithelial cells, initiating the expressions of a range of inflammatory cytokines, and prompting fibroblast proliferation.