培哚普利抗实验性大鼠肝纤维化的实验研究

Perindopril attenuates the progression of CCl_4-inducing rat hepatic fibrosis

目的 研究血管紧张素转化酶抑制剂-培哚普利对实验性肝纤维化的影响,并探讨其作用机制。 方法 取雄性大鼠40只,随机分为3组。模型组:40％ CCl4油0.25 g/L皮下注射,每周2次;培哚普利治疗组:40％CCl4油0.25 g/L皮下注射,2次/周,同时予以培哚普利2 mg/kg灌胃,1次/d。对照组:橄榄油皮下注射。于第4、6周取材。光镜下动态观察组织学改变,检测血管紧张素Ⅱ1型受体(A T 1 R)、转化生长因子β1(TGF—β1)、血小板衍生性生长因子-BB(PDGF—BB)蛋白的表达、金属蛋白酶-2(MMP-2)的活性和血清透明质酸(HA)、层黏连蛋白(LN)的含量。 结果 培哚普利治疗组肝组织炎症程度明显减轻,纤维间隔较为细小,血清HA、LN(μg/L)含量分别为82.07±13.66和94.84±3.54,模型组分别为147.86±18.92和113.72±2.14,t=2.27～2.87,P<0.05;培哚普利治疗组AT1R mRNA和蛋白质表达水平、TGF-β1和PDGF—BB蛋白质的表达低于模型组;模型组MMP-2活性高于培哚普利组。 结论 培哚普利对实验性大鼠肝纤维化具有抑制作用。

Objective The aim of the present study was to determine the effects of angiotensin-converting enzyme inhibitor, perindopril, on the progression of rat hepatic fibrosis induced by CCl4. Methods 40 male wistar rats weighting about 250 g were divided into 3 groups. Model group (Mo): the rats were injected with 40% CCl4 0.25 g/L subcutaneously three times a week. Perindopril group (Pe): the rats were injected with 40% CCl4. Perindopril, equivalent to 2 mg/kg/d, was given ig. Control group (Nc): the rats were injected with olive oil only. After 4,6 weeks, morphological examination was based on microscopy. RT-PCR was utilized to detect gene expression of angiotensin II type 1 receptor (ATI receptor) in the liver. Meanwhile, the protein expressions of AT1 receptor, transforming growth factor beta 1 (TGF- β1) and platelet-derived growth factor-BB (PDGF-BB) in liver tissue were examined by western blot. The activity of matrix metalloproteinase-2 (MMP-2) was assessed by zymography. Serum laminin (LN) and hyaluronic acid (HA) were measured using radio-immunity technique. Results RT-PCR and Western blot revealed that there was a up-regulation in AT1 receptor expression in model group compared with control group. Perindopril treatment significantly reduced mean fibrosis score, messenger RNA and protein levels of AT1 receptor, protein levels of TGF-β1 and PDGF-BB, Serum levels of HA and LN, and MMP-2 activity. Conclusions These results suggest that angiotensin n may play an important role in fibrosis of liver. Perindopril may have a inhibiting effect on CCl4-induced hepatic fibrogenesis of rat.