培哚普利和氯沙坦抗实验性肝纤维化的研究

Effect of ACE-I and AT-1 receptor blocker on the progression of CCl_4-inducing rat hepatic fibrogenesis

目的 探讨血管紧张素转化酶抑制剂 (ACE I)培哚普利和血管紧张素Ⅱ 1型受体 (AT 1受体 )阻滞剂氯沙坦对实验性肝纤维化的影响。方法 Wistar大鼠 6 0只 ,随机分为 4组 ,模型组 :4 0 %CCl4油 0 2 5ml/10 0mg皮下注射 ,每周 2次 ;培哚普利治疗组 :培哚普利 2mg/kg灌胃 ,每日 1次。氯沙坦治疗组 :氯沙坦 5 0mg/kg灌胃 ,每日 1次。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 ;RT PCR检测AT 1受体的表达 ;免疫蛋白质印迹检测AT 1受体、转化生长因子 β1(TGF β1)和血小板衍生生长因 BB(PDGF BB)蛋白的表达 ;明胶酶法测定金属蛋白酶 2(MMP 2 )的活性 ;放免检测血清透明质酸 (HA)、层粘蛋白 (LN)的含量。结果 培哚普利组和氯沙坦组肝纤维化程度和血清HA、LN含量低于模型组 ;培哚普利组和氯沙坦组AT 1受体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和氯沙坦组。结论 培哚普利和氯沙坦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 (ACE-I) and angiotensin Ⅱ type 1 receptor (AT-1 receptor) blocker on the progression of rat hepatic fibrosis induced by CCl 4 Methods 60 male wistar rats weighting about 250 g were divided into 4 groups Model group (Mo): The rats were injected with 40% CCl 4 025 ml/100 g subcutaneously three times a week Perindopril group (Pe): The rats were injected with 40% CCl 4 Perindopril, equivalent to 2 mg·kg -1·d -1, was given ig Losartan group (Lo): The rats were injected with 40% CCl 4 Losartan, equivalent to 50 mg·kg -1·d -1, 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 AT-1 receptor in the liver Meanwhile, the protein expressions of AT-1 receptor, TGF-β1 and 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 radioimmunoassays Results RT-PCR and Western blot revealed that there was a up-regulation in AT-1 receptor expression in model group compared with control group Both of perindopril and losartan 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 Conclusion These results suggest that angiotensin Ⅱmay play an important role in fibrosis of liver Perindopril and losartan may have inhibiting effects on CCl 4-induced hepatic fibrogenesis of rat