阿托伐他汀对百草枯中毒大鼠肺纤维化的影响及机制研究

The effects of atorvastatin on paraquat-induced pulmonary fibrosis and its mechanism

目的观察阿托伐他汀对急性百草枯(PQ)中毒大鼠肺间质成纤维细胞中基质金属蛋白酶及Smad3的表达影响,探讨其在PQ中毒致肺纤维化中的意义。方法 SD大鼠105只,随机分为对照组15只、百草枯组45只、阿托伐他汀组45只,后2组按时间点又随机分为3组。百草枯组、阿托伐他汀腹腔内注射百草枯35 mg/kg,对照组注射等体积无菌生理盐水,阿托伐他汀组给与阿托伐他汀1.5 mg/(kg.d)灌胃治疗。7、14、21 d后分离和提取肺间质成纤维细胞。采用RT-PCR检测肺组织MMP-2 mRNA、MMP-9 mRNA及Smad3 mRNA的表达。应用免疫细胞化学观察MMP-2、MMP-9、TGF-β1及用碱水解法检测HYP的表达量,观察肺病理学变化。结果与百草枯中毒比较,阿托伐他汀组MMP-2 mRNA、MMP-9 mRNA、Smad3 mRNA表达减少,MMP-2、MMP-9表达也减少,TGF-β1、HYP显著降低,具有统计学意义(P<0.05);病检发现:阿托伐他汀组炎细胞减少,可见成纤维细胞,周围较多正常肺组织,肺纤维化较白草枯中毒组明显减轻。结论阿托伐他汀具有抑制MMP-2 mRNA及MMP-9 mRNA的表达,进而减少MMP-2及MMP-9的表达,抑制Smad3 mRNA的表达,使TGF-β1及HYP生成减少,使肺间质纤维化明显减轻。

To evaluate the effects of atorvastatin on paraquat（PQ）-induced pulmonary fibrosis,we investigated atorvastatin-induced changes of matrix metal proteinases expression in pulmonary tissue fibroblasts of rats with acute paraquat poisoning.Total of 105 SD rats were randomly divided into control group,PQ poisoned group,and atorvastatin group.The rats in PQ group and atorvastatin group were treated intragastrically with PQ（50 mg/kg）,while the rats in control group were treated with the same dose of distilled water at the beginning of the experiment.Then the atorvastatin group received atorvastatin [1.5 mg/（kg·d）] administration and the other two groups received saline.At day 7,14,and 21,rats were sacrificed and pulmonary interstitial fibroblasts were separated and extracted to evaluate the expressions of MMP-2,MMP-9,and TGF-β1,the lung index,and the pathological changes in lung tissue.We found that in atorvastatin group,MMP-2,MMP-9,TGF-β1,hydroxyproline（HYP）,lung index were significantly reduced（P〈0.05）,as compared with paraquat poisoning group.Pathologic examination found that in paraquat group,normal alveolar structure disappeared,inflammatory cell permeated,fibroblast proliferated,and alveolar septum was obviously enlarged,with patchy collagen deposition and changes to fibrosis;while in atorvastatin group,fewer inflammatory cells penetrated,a small amount of fibroblasts found,collagen deposition and more normal lung tissue observed,and lung injury was significantly reduced as compared with paraquat group.According to above results,we concluded that atorvastatin can inhibit the expression of MMP-2,MMP-9,TGF-β1,and HYP,thus significantly reduce pulmonary fibrosis.