MMPs系统和细胞因子在慢性阻塞性肺疾病模型大鼠中的作用

Roles of matrix metalloproteinase system and inflammatory cytokines in rat with chronic obstructive pulmonary disease

目的观察慢性阻塞性肺疾病(COPD)模型大鼠基质金属蛋白酶及炎性细胞因子的变化。方法将30只大鼠随机分为正常组、模型组,每组15只。除正常组外,其余大鼠采用烟熏加脂多糖(LPS)气管滴入方法建立COPD大鼠模型,模型复制成功第28天,采用动物肺功能仪检测大鼠肺功能,酶联免疫吸附法观察大鼠血清白介素(IL)-1β、IL-10、IL-8、TGF-β1,免疫组化观察肺组织MMP-9及TIMP-1变化。结果模型组大鼠肺泡腔及肺间质内大量炎性细胞浸润,肺组织结构破坏。与正常组比较,模型组大鼠肺功能参数FEV0.3、FEV0.3/FVC、PEF值降低,Re升高(P<0.01,P<0.05);模型组大鼠IL-1β、IL-8、MMP-9表达水平较正常组明显升高,IL-10、TGF-β1、TIMP-1表达降低(P<0.05,P<0.01)。相关性分析显示肺功能参数FEV0.3与MMP-9呈负相关,FEV0.3/FVC与血清IL-1β呈负相关,PEF与血清IL-8呈负相关(P<0.05);FEV0.3/FVC、Re与TIMP-1呈正相关(P<0.05);MMP-9与IL-1β、IL-8呈正相关,TIMP-1与TGF-β1呈正相关(P<0.05,P<0.01);MMP-9与TGF-β1呈负相关(P<0.05)。结论 COPD的炎症反应与MMP-9/TIMP-1失衡有关,炎性细胞表达MMP-9占优势,炎症反应明显,最终导致肺功能降低。

To observe the change of matrix metalloproteinases and inflammatory cytokines in rat model of the chronic obstructive pulmonary disease （COPD）, total of 30 rats were recruited and randomly divided into normal group and model group （each group contains 15 rats）. Except rats in normal group, the remaining rats were treated with smoking and lipopolysaccharide （LPS） tracheal instillation to establish COPD model. Twenty-eight days after the model construction, a large amount of inflammatory cell infiltration and pulmonary alveolar interstitial intrinsic injury was found in rat model group. Spirometer showed that lung function parameters such as FEV0z, FEV0.3/FVC, PEF were decreased, but Re was increased in model group （P〈 0.01 or P〈 0.05）, as compared with normal control. Furthermore, immunohistochemistry staining indicated that the levels of IL-113, IL-8, and MMP-9 were significantly higher than that of normal control, but the expression levels of IL-10, TGF-[31, and TIMP-1 were decreased in model group （P〈 0.01 or P〈0.05）. Correlation analysis showed MMP-9 was positively related with IL-1[3 and IL-8 levels （P〈0.05）, but negatively correlated with FEV0.3, or TGF-[31 （P 〈 0.05）, while TIMP-1 was positively correlated with FEVJFVC, Re, and TGF-β1 （P〈 0.05, P〈 0.01）; in addition, FEV0.4FVC and IL-1β were negative correlated, PEF and IL-8 were negative correlated （P 〈 0.05）. In conclusion, COPD inflammation is related to imbalances of MMP-9/TMP-1. The dominant MMP-9, expressing by the inflammatory cells, can cause significantinflammation, and result in reduction of pulmonary function.