摘要目的：研究sonic hedgehog（ Shh）信号通路在慢性氟中毒大鼠肝脏组织中的表达情况以及环杷明（ cyclopamine）的抑制作用，探讨Shh信号通路对慢性氟中毒大鼠肝脏损伤作用的机制及其意义。方法建立慢性氟中毒大鼠动物模型，选取4～5周龄，健康SD大鼠48只，饲养1周后按体质量均衡分为4组，每组12只，正常组、氟中毒组、阻断剂组以及阻断剂对照组。饲养6个月后阻断剂组腹腔注射环杷明，阻断剂对照组腹腔注射二甲基亚砜，10 mg／kg，隔天1次，注射3次。收集大鼠24 h尿液检测尿氟后处死大鼠，应用自动血生化分析仪检测大鼠肝功能，通过免疫组织化学（ IHC ）、Western blot和即时荧光定量PCR （ real－time PCR ）的方法检测大鼠肝脏组织中 Shh、Gli1蛋白和mRNA的表达。结果（1）与对照组相比，染氟组大鼠氟斑牙发生率明显升高，各组尿氟含量均增加。（2）肝功能检查显示，与对照组相比，染氟组的肝脏功能明显地改变，氟中毒组、阻断剂对照组中丙氨酸转氨酶和天冬氨酸转氨酶活性升高，而总蛋白和白蛋白含量降低；与染氟组比较，阻断剂组丙氨酸转氨酶活性降低，而天冬氨酸转氨酶、总蛋白和白蛋白含量升高。（3）肝形态学改变：光镜下观察发现，与对照组相比，实验组大鼠肝脏肝细胞索排列紊乱，肝细胞肿大，部分肝细胞胞质透亮，呈气球样改变。（4）与对照组相比，氟中毒组、阻断剂对照组中Shh、Gli1蛋白和mRNA的表达升高，阻断剂组较氟中毒组、阻断剂对照组降低。结论过量氟可以激活慢性氟中毒大鼠肝组织中Shh信号通路，环杷明能有效地抑制Shh信号通路激活，故Shh信号通路可能参与慢性氟中毒引起肝脏损伤发病的过程，研究该通路的作用机制对慢性氟中毒肝脏损伤的预防、诊疗有较大的意义。

abstractsObjective To investigate the expression of sonic hedgehog( Shh) signaling pathway in liver fluorosis and to explore related mechanism.Methods To establish animal model, 48 normal SD rats ( aged 4-5 weeks) were randomly divided into 4 groups(12 each):control group, fluoriosis group, blocking group and blocking control group.After 6 months, the blocking group and blocking control group were injected intraperitoneally once every 2 days for 3 times with 10 mg/kg cyclopamine or dimethysulfoxide, respectively.Rats were sacrificed at the end of the experiment and the fluoride content in urine and liver function was determined.The expression of Shh and Gli1 protein and mRNA in hepatocytes was detected by immunohistochemistry and real-time fluorescence quantitative PCR, respectively.Results The fluoride contents in the urine and the incidence of dental fluorosis increased in the fluoride and blocking control groups as compared with those in the control group, but decreased in the blocking group compared with those of the fluoride and blocking control group. Compared with the control group, the titers of aspartate transaminase (AST) and alanine transaminase ( ALT) significantly increased, while the activity of total protein and albumin decreased in the fluoride and blocking control groups.Compared with the fluoride and blocking control groups, the activity of the ALT slightly declined and the AST, total protein and albumin slightly increased in the blocking group. Histologically, the cells were disorganized and swollen with cytoplasmic clearing ( balloon cells ) , compared with the control group.The expression of Shh and Gli1 significantly increased in all but the control group.Compared with the fluoride and blocking control groups, the expression of Shh and Gli1 declined in the blocking group.Conclusions The overexpression and cyclopamine inhibition of the Shh signaling pathway are closely related to the content of fluoride in the liver. The Shh signaling pathway plays an important role in the pathogenesis of liver injury caused by fluorosis, suggesting a preventive and therapeutic target of the disease.