基质金属蛋白酶9及金属蛋白酶组织抑制剂1在肺血栓栓塞相关肺血管重构中的作用探讨  

Effect of matrix metalloproteinase-9 and its tissue inhibitor-1 in pulmonary vascular remodeling associated with pulmonary thromboembolism

作　　者：张黎明[1] 王辰[1] 庞宝森[1] 朱敏[1] 

机构地区：[1]首都医科大学附属北京朝阳医院(京西院区)呼吸科北京呼吸疾病研究所,100043

出　　处：《国际呼吸杂志》2008年第3期129-132,F0003,共5页International Journal of Respiration

基　　金：科技部“十五”攻关项目（2001BA703B13）

摘　　要：目的通过颈外静脉注入自体血凝块并应用氨甲环酸建立大鼠肺血栓栓塞症（PTE）相关肺血管重构动物模型，探讨基质金属蛋白酶9（MMP-9）及金属蛋白酶组织抑制剂1（TIMP-1）在PTE相关肺血管重构中的作用。方法将56只SD大鼠随机分为PTE组及假手术组（Sham组）。PTE组用注入血栓及抑制纤溶方法制作PTE模型。Sham组用生理盐水代替血栓及抗纤溶药物。每组分别于制模后1、3、7、14d各取7只鼠处死，留血检测MMP-9、TIMP-1含量。取左肺做苏木素伊红染色、磷钨酸苏木素（PTAH）染色及α-平滑肌肌动蛋白（α-SMA）免疫组织化学（IH）染色，并做MMP-9、TIMP-1 IH及原位杂交（ISH）染色。结果①PTE组制模第7天见到栓塞部位肺血管重构，14d时更加明显。②PTE组血清MMP-9浓度及MMP-9／TIMP-1比值均高于Sham组（P〈0．01），TIMP-1在1d及3d时显著高于Sham组（P〈0．05，P〈0．01），7d与14d时降至Sham组水平。③PTE组IH染色显示栓塞部位的血管及新生内膜中的平滑肌细胞、内皮细胞及浸润的单核-巨噬细胞，MMP-9染色阳性。栓塞部位的血管内皮细胞及平滑肌细胞TIMP-1染色阳性。Sham组MMP-9及TIMP-1染色阴性或弱阳性。MMP-9及TIMP-1 ISH染色结果与IH染色结果基本一致。④α-SMA染色显示平滑肌细胞是新生内膜的主要成分。结论颈外静脉注入自体血栓并重复应用抗纤溶药物可成功建立大鼠PTE相关肺血管重构模型，PTE相关肺血管重构的主要病理改变为新生内膜生成。MMP-9／TIMP-1失调参与了PTE相关肺血管重构过程。Objective By inducing a model of pulmonary vascular remodeling associated with pulmonary thromboembolism （PTE） in rats by external jugular vein iniection of thrombus cylinders and the use of tranexamic acid, to investigate the effect of matrix metalloproteinase-9（MMP-9） and tissue inhibitor of metalloproteinase-1 （TIMP-1） in pulmonary vascular remodeling associated with PTE. Methods Fifty-six male Sprague Dawley（SD） rats were divided randomly into PTE group and sham group. PTE model was induced by external jugular vein injection of thrombus cylinders and intraperitoneal injection of tranexamic acid in PTE group. Sham group was exposed to same surgical stressors as the PTE rats but without thrombus cylinders and tranexamic acid. Seven rats were sacrificed from each group on 1,3,7 and 14 d after operation. The arterial blood sample was taken to detect the contents MMP-9 and TIMP- 1. The left lung was harvested for Haematoxyllin-Eosin（HE） staining, phosphotungstic acid hematoxylin （PTAH） staining, the immunohistochemistry （IH） stainings of MMP-9, TIMP-1 and a-smooth muscle actin （α-SMA）, the hybridization in situ staining of MMP-9 and TIMP-1. Results （1）Pulmonary vascular remodeling was seen in PTE group on the 7th day and more obvious on the 14th day. （2）The serum concentrations of MMP-9 and the ratio of MMP-9/TIMP-1 in PTE group were higher compared with those of sham group（ P 〈0.01 ）. The serum concentrations of TIMP-1 in PTE group were higher compared with those of sham group on 1st and 3rd day（ P 〈0.05, P 〈0.01）and decreased to the level of sham group on the 7th and 14th day. （3）MMP-9 was expressed strongly in IH staining in the smooth muscle cells, the endothelial cells, the smooth muscle cells of neointima and the infiltrating monocyte-macrophages in the embolic vessel in PTE group. There was positive expression of TIMP-1 with the IH staining in vascular endothelial cells and smooth muscle cells in PTE group. There was no or weak expression of MMP-9 a

关 键 词：肺血栓栓塞症 血管重构 基质金属蛋白酶 基质金属蛋白酶组织抑制剂 细胞外基质 

分 类 号：R563.5[医药卫生—呼吸系统]