维甲酸对大鼠肺气肿模型肺组织中MMP-12、TIMP-2及TNF-α表达的调节  

Regulatory effect of tretinoin on expressions of MMP-12, TIMP-2, and TNF-α in rat model of PPE-induced emphysema

作　　者：郭亚利[1] 马晋[2] 徐建林[1] 汪伟民[1] 

机构地区：[1]安徽医科大学第一附属医院老年呼吸内科,安徽合肥230022 [2]合肥市第一人民医院呼吸内科,安徽合肥230022

出　　处：《中国新药与临床杂志》2009年第3期204-208,共5页Chinese Journal of New Drugs and Clinical Remedies

基　　金：安徽省教育厅自然科学研究项目(KJ2009A118)

摘　　要：目的探讨维甲酸(TR)对猪胰弹性蛋白酶(PPE)诱导的肺气肿大鼠模型肺组织中基质金属蛋白酶12(MMP-12)、金属蛋白酶组织抑制剂2(TIMP-2)及肿瘤坏死因子α(TNF-α)的调节作用。方法60只SD大鼠随机分为6组(均n=10):对照组、模型组、TR低剂量治疗组、TR中剂量治疗组、TR高剂量治疗组和棉籽油组。PPE诱导肺气肿大鼠模型成功后,TR各治疗组和棉籽油组于d76分别每日向大鼠腹腔内注射低、中、高剂量TR(500、1000、2000μg·kg-1)和棉籽油(1mL·kg-1),连续14d,90d后处死大鼠。HE染色观察各组大鼠肺组织的病理改变,免疫组化法观察肺组织内MMP-12、TIMP-2及TNF-α的蛋白表达情况,酶联免疫吸附实验(ELISA)检测血清中TNF-α的含量。结果光镜下观察,模型组、棉籽油组及TR高剂量治疗组可见肺泡管、肺泡囊和肺泡明显扩张,肺泡壁变薄,并有不同程度的断裂,类似于人类小叶中央型肺气肿,而低、中剂量TR治疗组则病变程度较轻。与对照组相比,模型组及TR各治疗组肺组织的MMP-12、TIMP-2和TNF-α的蛋白表达明显增强(P<0.01)。TR各治疗组与模型组肺组织的MMP-12表达无明显差异(P>0.05)。TR各治疗组肺组织的TIMP-2表达高于模型组(P<0.01),但各治疗组之间无显著差异。TR中剂量治疗组的MMP-12/TIMP-2比值明显低于模型组,差异显著(P<0.003)。TR各治疗组肺组织的TNF-α表达低于模型组;血清中TNF-α的含量,模型组高于对照组(P<0.01),TR各治疗组与模型组间无明显差异(P>0.05)。结论TR在一定程度上可减轻PPE诱导的大鼠肺气肿严重程度,其机制可能为:通过调节MMP-12/TIMP-2的平衡,抑制肺组织局部TNF-α的表达,从而促进肺组织的修复。AIM To study the regulation of tretinoin （TR） to the matrix-metalloproteinase （MMP）-12, tissue inhibitor of metalloproteinase （TIMP）-2 and tumor necrosis factor-alpha （TNF-α） in rat model of the porcine pancreatic elastase （PPE） induced emphysema and its possible significance. METHODS Sixty Sprague- Dawley rats were randomly divided into six groups （n = 10） ： control group, model group, TR low-dose treatment group, TR middle-dose treatment group, TR high-dose treatment group, and cottonseed oil group. TR treatment groups and cottonseed oil group were intraperitoneally injected respectively with TR （500, 1 000, and 2 000 μg ·kg^-1） and cottonseed oil （1 mL·kg^-1） daily for 2 weeks when the emphysema models were constructed. Histological changes of lung tissue were evaluated by HE staining. The protein expressions of MMP- 12, TIMP-2, and TNF-α in lung tissue were detected by immunohistochemistry method. The serum concentration of TNF-α was detected by enzyme-linked immunosorbent assay （ELISA）. RESULTS Under the light microscope, the alveolar duct, alveolar sacs and alveolar were enlarged in model group, TR high-dose treatment group, and cottonseed oil group. Alveolar wall became thinning and disrupted, resembling the central lobular emphysema of human. While the lesions of TR low-dose and middle-dose treatment group were less severe in degree and extent. Compared with control group, the protein expressions of MMP-12, TIMP-2, and TNF-α in lung tissue were markedly elevated （P 〈 0.01 ） in other five groups, but the expressions of MMP-12 in TR treatment groups were not different from the model group （P 〉 0.05）. Compared with the model group, the TIMP-2 expressions in lung tissue in TR treatment groups were increased significantly （P 〈 0.01 ）. The ratio of MMP-12/TIMP-2 in the TR middle-dose treatment group was lower than that in the model group （P 〈 0.003）. Compared with the model group, the TNF-α expressions in lung tissue in TR treatment groups we

关 键 词：维甲酸 肺气肿 基质金属蛋白酶12 金属蛋白酶2组织抑制剂 肿瘤坏死因子α 

分 类 号：R563.3[医药卫生—呼吸系统]