中文摘要：

目的研究塞来昔布（CXB）对Han：SPRD大鼠肾细胞外基质（ECM）重塑的影响，探讨其抑制多囊肾肾间质纤维化的作用机制。方法选取杂合（cy／＋）交配后第4代雄性、3周龄、体质量（68．54-16．6）g的Han：SPRD大鼠共57只，随机分成对照组（CXB：0mg·kg^-1·d^-1）、CXB小剂量组（CBX：3mg·kg^-1·d^-1）、CXB大剂量组（CBX：10mg·kg^-1·d^-1），每组19只。另选19只SD大鼠作为正常对照。饲料中加入CXB喂食13周后，处死动物。倒置显微镜下分析肾组织纤维化指数；实时荧光定量PCR检测肾组织胶原Ⅳ（COLⅣ）、基质金属蛋白酶（MMP）2、金属蛋白酶2组织抑制剂（TIMP）和转化生长因子（TGF）B1mRNA的表达；免疫荧光共聚焦扫描法检测COLIV、MMP-2、TIMP-2、TGF-β1与PCNA共染的蛋白丰度；蛋白免疫印迹法检测TGF-81的表达。结果与对照组相比，小剂量组和大剂量组均能显著减少肾囊肿指数（42．90±6．56和47．10±7．28比64．80±62．71，均P〈0．05）、纤维化指数（11．20±2．63和10．10±3．30比16．30＋4．16，均P〈0．05）和间质炎性细胞的浸润（2．60±0．26和2．80±0．31比3．70±0．33，均P〈0．05）。小剂量组和大剂量组COLⅣ、TIMP-2和TGF．B1mRNA的表达量显著低于对照组（均P〈O．05），而MMP-2mRNA的表达量显著高于对照组（均P〈0．05）。小剂量组和大剂量组COLlV荧光强度较对照组显著减弱，差异有统计学意义（20．30±5．11比61．40±4．51，P〈0．01；27．50±6．73比61．40±4．51，P〈0．05）。小剂量组和大剂量组MMP．2／TIMP-2比值较对照组增高，差异有统计学意义（4．88＋1．52和3．63±1．67比0．35±0．13，均P〈0．05）。小剂量组和大剂量组TGF—β1蛋白表达比对照组均显著减少。结论塞来昔布可能通过下调TGF-β1、增加MMP-2／TIMP-2比值、促进胶原Ⅳ的降解来抑制肾小管间质的纤维化。

英文摘要：

Objective To investigate the effect of celecoxib （CXB） on extracellular matrix （ECM） remodeling in a model of autosomal dominant polycystic kidney （ADPKD）. Methods Fifty seven Han： SPRD heterozygous （Cy/＋） rats were randomly divided into 3 groups： control group, small dosage CXB group （3 mg·kg^-1·d^-1） and large dosage CXB group （10 mg·kg^-1·d^-1）. Renal cystic index （CT）, fibrosis index and inflammatory cells imqhration in interstitium were analyzed. The mRNA expression of typeiV collagen （COL1V）, matrix matalloproteinase-2 （MMP-2）, metalloproteinase-2 tissue inhibitor （TIMP-2） and transforming growth factor β1 （TGF-β1） wasdetected by real-time PCR. The co-expression of COL IV, MMP-2, TIMP-2, TGF-β1 and proliferating cell nuclear antigen （PCNA） was analyzed by double immnnofluorescence labeling technique and laser scanning confocal microscopy. The protein expression of TGF-β1 was detected by Western blotting. Results CT （42.90±6.56 ＆ 47.10±7.28 vs 64.80±6.71, all P〈0.05）, fibrosis index （11.20±2.63 ＆ 10.10±3.30 vs 16.30±4.16, all P〈0.05） and inflammatory cells infiltration （2.60±0.26 ＆ 2.80±0.31 vs 3.70±0.33, all P〈0.05） in interstitium all decreased in small and large dosage group compared to control group. COLIV ,TIMP-2 and TGF-β1 mRNA level decreased in both small and large dosage groups as well. Contrarily MMP-2 mRNA level increased in both groups（all P〈0.05）. The eo-expression of COLIV distributed widely in tubulointerstitial area in control group but only few in small （20.30±5.11 vs 61.40±4.51, P〈0.01） and large dosage group （27.50±6.73 vs 61.40±4.51, P〈0.05）. MMP-2/TIMP-2 ratio increased in smalll dosage group （4.88±1.52 vs 0.35±0.13, P〈0.05） and large dosage group （3.63±1.67 vs 0.354±0.13, P〈 0.05） as compared to control group. Western blotting showed the expression of TGF-β1 decreased in both small and large dosage groups （all P〈0.05）. Conclusion CXB can inhibit tu