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目的探索Hedgehog通路抑制剂环巴明(cyclopamine,Cyc)对正常和肝硬变大鼠门静脉压力的影响及其可能机理,为进一步的药物疗效研究和临床治疗提供实验依据。方法取健康雄性SD大鼠32只,随机均分正常对照组、正常给药组、肝硬变对照组及肝硬变给药组4组。采用硫代乙酰胺(thioacetamide,TAA)法复制大鼠肝硬变模型,即以0.03%TAA作为初始饮用水浓度,然后根据每周体重变化调整饮用水中TAA浓度,共饲喂12周。第13周开始,正常对照组和肝硬变对照组大鼠接受腹腔注射玉米油,0.1 ml/100 g体重,1次/d,连续1周;正常给药组和肝硬变给药组大鼠接受腹腔注射Cyc,1 mg(0.1 ml)/100 g体重,1次/d,连续1周。第14周时测定各组大鼠的肝功能、门静脉压力(portal venous pressure,PVP)及肝脾重量比,采用免疫组化方法检测肝星状细胞(hepatic stellate cell,HSC)α-平滑肌肌动蛋白(α-smooth muscle actin,α-SMA)和Ⅰ型胶原蛋白(typeⅠcol-lagenα1,Col1α1)的表达。结果正常对照组大鼠PVP为(10.7±0.9)cm H2O(1 cm H2O=0.098 kPa),正常给药组PVP为(12.3±1.3)cm H2O,后者高于前者,差异有统计学意义(t=-2.918,P=0.011);肝硬变对照组PVP为(21.8±0.7)cm H2O,肝硬变给药组PVP为(14.3±1.4)cm H2O,后者低于前者(t=13.602,P=0.000)。肝硬变给药组α-SMA和Col1α1的表达均比肝硬变对照组减少。正常给药组和肝硬变给药组的肝功能变化及肝脾重量与其各自对照组之间相比,差异均无统计学意义(P>0.05)。结论 Cyc通过减少α-SMA和Col1α1的表达,显著降低肝硬变大鼠的PVP。
Objective To explore the effect and possible mechanism of Hedgehog pathway inhibitor cyclopamine (Cyc) on portal pressure in normal and cirrhotic rats and provide experimental basis for further study on drug efficacy and clinical treatment. Methods Thirty-two male SD rats were randomly divided into four groups: normal control group, normal control group, cirrhosis control group and cirrhosis administration group. Rat model of liver cirrhosis was induced by thioacetamide (TAA) method, that is, TAA concentration of 0.03% was used as initial drinking water level. TAA concentration in drinking water was adjusted according to weekly body weight changes for a total of 12 weeks. From the 13th week, the rats in the normal control group and cirrhosis control group received intraperitoneal injection of corn oil, 0.1 ml / 100 g body weight once a day for 1 week. In the normal group and the cirrhosis group, Rats received intraperitoneal injection of Cyc, 1 mg (0.1 ml) / 100 g body weight once daily for 1 week. At the 14th week, the liver function, portal venous pressure (PVP) and the ratio of liver and spleen of the rats in each group were measured, and the α-smooth muscle activity of hepatic stellate cells (HSC) was detected by immunohistochemistry Α-smooth muscle actin (α-SMA) and typeⅠcol-lagenα1 (Col1α1). Results The PVP in the normal control group was (10.7 ± 0.9) cm H2O (1 cm H2O = 0.098 kPa) and that in the normal group was (12.3 ± 1.3) cm H2O, which was higher than the former PVP was (21.8 ± 0.7) cm H2O in liver cirrhosis control group and PVP was (14.3 ± 1.4) cm H2O in cirrhosis group, which was lower than the former (t = -2.918, P = 0.011) , P = 0.000). The expression of α-SMA and Col1α1 in the cirrhotic group were lower than those in the control group. There was no significant difference in the changes of liver function, liver and spleen weight between the normal group and the cirrhotic group and their respective control groups (P> 0.05). Conclusion Cyc can significantly reduce PVP in cirrhotic rats by decreasing the expression of α-SMA and Col1α1.