选择性COX-2抑制剂、PGE1对肝硬化大鼠VEGF和CTGF表达的影响

目的探讨环氧合酶-2（COX-2）抑制剂、PGE1对肝硬化大鼠肝脏血管内皮生长因子（VEGF）和结缔组织生长因子（CT-GF）表达的影响。方法用50％CCl4（CCl4／橄榄油：体积比1／1）腹腔注射诱导SD大鼠肝硬化模型，每周2次，共8周。52只SD大鼠随机分为4组：正常对照组（n=10）腹腔注射橄榄油；模型对照组（n=14），在诱导模型的同时给予等体积生理盐水灌胃，每日1次；选择性COX-2抑制剂罗非昔布组（n=14），按10mg·kg^-1·d^-1灌胃；米索前列醇即PGE，组（n=14），按每只大鼠10μg·d^-1灌胃。8周末处死大鼠留取肝组织，通过Westernblot和免疫组织化学方法检测肝组织VEGF和CTGF表达和定位。结果随着CCl4诱导大鼠肝硬化的形成，肝组织VEGF和CTGF的表达增加，与肝硬化模型对照组（安慰剂）比较，选择性COX-2抑制剂罗非昔布能显著降低肝脏VEGF和CTGF蛋白表达水平，而PGE1对VEGF无影响，CTGF显著降低。结论肝纤维化形成过程中，肝组织VEGF和CTGF的表达增加，选择性COX-2抑制罗非昔布能在体内抑制肝组织CTGF和VEGF的表达，这可能是罗非昔布抗肝纤维化的分子机制。

Effect of selective COX-2 inhibitor and PGE1 on the expression of VEGF and CTGF in cirrhotic rats

Objective To assess the effect of selective Cyclooxygenase-2 （COX-2） inhibitor, and PGE1 on the expression of vascular endothelial growth factor （VEGF） and connective tissue growth factor （CTGF） in cirrhotic rats. Methods Fifty-two male Sprague-Dawley rats were used. Cirrhosis was induced by CCl4 （CCl4/olive oil： v/v = 1/1 ） twice a week for 8 weeks. Rats in the control group （n = 10） received olive oil only; CCl4 treated rats were divided into three groups： the model group （n = 14） in which placebo （saline solution by gavage） was administered, rofecoxib （10 mg·kg^-1· d ^-1 by gavage） group （n=14） and misoprostol （10 μg·d^-1 by garage） group （n=14）. The CTGF and VEGF protein levels and their localization in the liver were determined by Western blot and immunohistochemistry, respectively. Results The protein levels of VEGF and CTGF both elevated in the liver of rats treated with CCl4. Compared with placebo, protein expressions of VEGF and CTGF were both significantly suppressed by rofecoxib treatment, while CTGF protein level decreased and VEGF protein level did not alter in the misoprostol group liver. Conclusion As liver fibrogenesis progressing, both VEGF and CTGF increased in liver, but the selective COX-2 inhibitor, rofecoxib may inhibit these increase. This may be the molecular basis of the COX-2 inhibitor to ameliorate hepatic fibrosis.