选择性环氧合酶-2抑制剂塞莱希布对大鼠肝纤维化的作用  

Selective COX-2 inhibitor celecoxib inhibits liver fibrogenesis in rats

作　　者：田丰[1] 王琳 张亚杰[1] 

机构地区：[1]中国医科大学附属盛京医院消化内科,辽宁省沈阳市110004 [2]大连市第六人民医院消化内科,辽宁省大连市116031

出　　处：《世界华人消化杂志》2011年第19期2002-2010,共9页World Chinese Journal of Digestology

基　　金：辽宁省教育高等学校科学技术研究基金资助项目;No.05L556~~

摘　　要：目的:探讨选择性COX-2抑制剂塞莱昔布对CCl4诱导的大鼠肝纤维化的作用.方法:5-6周龄的♂SD大鼠50只,随机分为6组.A组(肝纤维化模型组):10只,50%CCl4橄榄油溶液1mL/kg,每周2次皮下注射,同时给予生理盐水灌胃;B组(早期治疗组):10只,造模同时给予塞莱昔布15mg/kg溶于生理盐水中灌胃,每天1次;C组(中期治疗组):10只,造模同时给予生理盐水灌胃,第3周起改为塞莱昔布灌胃;D组(晚期治疗组):10只,造模同时给予生理盐水灌胃,第5周起改为塞莱昔布灌胃;E组:5只,给予相同体积的橄榄油皮下注射,同时给予相同剂量的塞莱昔布灌胃;F组:5只,给予相同体积的橄榄油皮下注射和生理盐水中灌胃.上述处置共8wk.实验结束后腹主动脉取血,取肝组织,检测血清谷丙转氨酶(ALT)、透明质酸(HA)、层粘连蛋白(LN)水平;病理组织学HE染色及Masson染色观察肝纤维化严重程度并评分,免疫组织化学方法检测肝组织Ⅰ胶原、α-SMA、COX-1、COX-2的表达.结果:A组与F组相比,可见显著的肝纤维化改变(P<0.01);与A组相比,B组病理染色可见肝纤维化程度明显减轻(P<0.01),血清ALT、HA、LN水平明显降低(100.4U/L±8.7U/Lvs287.8U/L±9.6U/L,189.6μg/L±83.0μg/Lvs382.6μg/L±136.0μg/L,71.4μg/L±4.6μg/Lvs108.7μg/L±9.8μg/L,均P<0.01),免疫组织化学示Ⅰ型原、α-SMA、COX-2阳性表达面积减少(P<0.01);B组、C组、D组间两两比较,各项指标差异有统计学意义(P<0.05);E组与F组比较无显著性差异;COX-1阳性表达各组间无显著性差异.结论:COX-2在肝纤维化的形成过程中发挥重要作用;选择性COX-2抑制剂塞莱昔布具有抗肝纤维的作用,并呈时间依赖性,越早给药效果越好,其机制可能是抑制肝星状细胞的活化和炎症反应.AIM：To investigate whether celecoxib,a selec- tive cyclooxygenase-2（COX-2）inhibitor,protects from carbon tetrachloride（CCl4）-induced liver fibrosis in rats. METHODS：Fifty male SD rats were randomly divided into six groups.Group A（n=10）was subcutaneously injected with 50%1 mL/kg CCl4 olive oil solution,twice per week,to induce hepatic fibrosis and intragastrically given saline. Groups B（n=10）,C（n=10）and D（n=10）were also subjected to induction of hepatic fibrosis and intragastrically given celecoxib 15 mg/kg once daily from day 1,week 3,and week 5 after CCl4 injection.Group E（n=5）was subcutaneously injected with equal volume of olive oiland intragastrically given the same dose of celecoxib,while group F（n=5）was subcutaneously injected with equal volume of olive oil and intragastrically given saline.The treatment lasted for 8 weeks.At the end of the experiment,blood samples were collected to measure serum ALT, HA and LN levels,while hepatic tissue samples were taken to evaluate the degree of liver fibrosis by HE staining and to detect the expression of type I collagen,alpha SMA,COX-1,and COX-2 by immunohistochemistry. RESULTS：Compared to group F,significant hepatic fibrosis was observed in group A（P 0.01）.Compared to group A,liver fibrosis was significantly reduced（P0.01）,serum ALT,HA and LN levels significantly decreased（100.4 U/L ±8.7 U/L vs 287.8 U/L±9.6 U/L,189.6μg/L± 83.0μg/L vs 382.6μg/L±136.0μg/L,71.4μg/L ±4.6μg/L vs 108.7μg/L±9.8μg/L,all P0.01）, and the areas positive for type I collagen,alpha SMA,and COX-2 were reduced（all P0.01）. The above parameters showed significant differences among groups B,C and D（all P0.05）. No significant differences were observed in the above parameters between groups E and F. COX-1-positive area showed no significant difference among each group. CONCLUSION：COX-2 plays an important role in liver fibrogenesis.Celecoxib can reduce or prevent liver fibrosis in a time-dependent manner probably by inhibiting hepa

关 键 词：环氧合酶-2 选择性环氧合酶-2抑制剂 肝纤维化 塞莱昔布 

分 类 号：R575.2[医药卫生—消化系统]