基质金属蛋白酶-7底物在大鼠肺动脉高压形成过程中的作用

Effect of matrix metalloproteinases-7 substrate on the development of pulmonary hypertension in rats

目的观察注射基质金属蛋白酶(matrix metalloproteinases,MMP)-7底物导致MMP及其抑制物(tissue inhibitors of metalloproteinase,TIMP)失衡在野百合碱(monocrotaline,MCT)诱导肺动脉高压中的作用。方法 45只SD(Sprague-Dawley)大鼠随机(电脑随机数字表法)分为3组:对照组、MCT组、MMP-7组各15只。MCT组、MMP-7组单次腹腔注射2%MCT 50 mg/kg造模;MMP-7组皮下注射MMP-7底物(1 mg/kg),MCT组皮下注射0.9%氯化钠溶液对照;对照组腹腔及皮下注射0.9%氯化钠溶液对照。4周后,测定大鼠肺动脉压力及血浆MMP-7、TIMP-1、TIMP-2、TIMP-3浓度,同时行病理切片测定肺小动脉中层厚度。结果 MMP-7组血浆MMP-7、TIMP-3浓度较其他两组明显升高,差异有统计学意义(P<0.01);MCT组血浆MMP-7浓度较对照组升高,差异有统计学意义(P<0.01)。3组血浆TIMP-1、TIMP-2浓度比较,差异无统计学意义(P>0.05)。MCT组、MMP-7组肺小动脉中层均明显增厚,MMP-7组较MCT组小,但差异无统计学意义(P>0.05)。结论皮下注射MMP-7底物可提高MMP-7、TIMP-3浓度,在一定程度上通过降低肺动脉压力及肺小动脉重构来减缓肺动脉高压。

Objectives To observe the role of matrix metalloproteinases （MMPs）/tissue inhibitors of metalloproteinases （TIMPs） imbalances in the formation of pulmonary hypertension （PAH） induced by monoerotaline （MCT）. Methods Fourty-five healthy male Sprague-Dawley rats were randomly divided into three groups： control group, MCT group and MMP-7 group with 15 rats in each group. From the first day to the third day, rats in MCT group and MMP-7 group received a single intraperitoneal injection of 2% MCT 50 mg/kg to establish a PAH model. Rats in MMP-7 group was injected with MMP-7 substrate 1 mg/kg subcutaneously, rats in MCT group was injected with saline and rats in control group received intraperitoneal and subcutaneous injection with saline. After 4 weeks, pulmonary artery pressure was detected and plasma concentrations of MMP-7, TIMP- 1,2,3 were measured. At the same time, pulmonary artery intima-media thickness was determined by pathological section. Results Plasma concentrations of MMP-7 and TIMP-3 of MMP-7 group increased significantly compared with those of the other two groups （P〈0.01）. Plasma concentration of MMP-7 of MCT group was significantly higher than that of control group （P〈0.01）. There was no significant difference in plasma concentrations of TIMP-1 and 2 among the three groups （P〉0.05）. Pulmonary artery intima-media thickness of MMP-7 group and MCT group was obviously thicker than that of control group ; and thickness of MMP-7 group was thinner than that of MCT group, but there was no significant difference （P〉0.05）. Conclusions Subcutaneous injection of MMP-7 substrates can improve the plasma concentrations of MMP-7 and TIMP-3. To a certain extent, it can reduce pulmonary artery pressure and pulmonary arteriole reconstruction to reduce PAH.