基质金属蛋白酶-9抑制剂巴马司他对心肺转流急性肺损伤的保护作用

摘要

Objective To investigate the protective effect of exogenous inhibitor of matrix metallopmteinases-9(MMP-9),batimastat,in the lung injury induced by cardiopulmonary bypass(CPB)in dogs.Methods Thirty healthy mongrel puppies were randomly divided into 3 groups:control group,lowdose group [batimastat 10 mg/(kg-d) for 3 days before operation]and high-dose group[batirnastat 30 established.and hemodynamic and respiratory parameters were monitored.The preoperative and postoperative alveolar-arterial oxygen difference(A-aDO_2)and respiratory index (RI) were calculated.From the beginning of surgery,blood samples were taken at the time 0,60,120,and 270 min Plasma concentrations of MMP-9 were measured by ELISA,and blood MMP-9 mRNA expressions were deterrnined bv RT-PCR The myelopemxidase (MPO) activity of centrifugal bronchoalveolar lavage fluid were measured by Colorimetry.And MMP-9 activity was determined by Gelatin zymography.Light and electronic microscope were used to observe the morphological changes of lung tissue.A small piece of left lung tissue wag taken.weighed and baked to calculate the wet weiight(W/D)index.Results After cardiopulmonary bypass,the concentrations of MMP-9 and mRNA expressions of the control group were increased significantly.and lung injury was apparent.At 270 min,the MMP-9 plasma concentration of high-dose group(17.36±1.18)μLwas significant reducing than control group(30.47±2.22)μg/L(P<0.05),After operation,A-aDO_2 and RI of hiSh-dose group were significantly impmved than control group(P<0.05).,The W/D index of the high-dose group(2.8±0.48) was significantly lower than that of control group (4.7±0.6)(P<0.05). And the pathological changes of lung tissue were significantly improved in the high-dose group.However.there Was no significant difference in the MMP-9 mRNA expression in three groups.Conclusions Batimastat plays a role in the protection of the lung injury of CBP by reducing the concentration and activity of MMP-9, the degradation of the cell membrane and pulmonary neutrophil infiltration and reduction of pulmonary edema.%目的 研究外源性基质金属蛋白酶-9(MMP-9)抑制剂巴马司他在心肺转流急性肺损伤中的保护作用.方法 30只健康杂种幼犬随机分为对照组、低剂量组和高剂量组.低剂量组术前 连续3 d每天腹腔注射巴马司他10 mg/ks,高剂量组术前连续3 d每天腹腔注射巴马司他30 mg/kg.分别计算术前和术后肺泡-动脉氧分压差(A-aDO_2)和呼吸指数(RI).从手术前开始计时,分别于0、60、120和270 min时采集静脉血样,酶联免疫吸附法测血浆MMP-9浓度,RT-PCR法测定血MMP-9 mRNA表达变化.比色法测定支气管肺泡灌洗液(BALF)髓过氧化物酶活性,明胶酶谱法测定BALF MMP-9活性.计算肺湿/干质量比.光镜和电镜下观察肺组织形态学改变.结果 270 min时高剂 量组血浆MMP-9浓度(17.36±1.18)μg/L,低于对照组的(30.47±2.22)μg/L(P<0.05).高剂量组 术后A-aDO_2和RI较对照组明显改善(P<0.05),高剂量组肺湿/干质量比(2.8±0.5)较对照组(4.7 ±0.6)明显减低(P<0.05),且肺组织的病理改变显著减轻;但三组间血MMP-9 mRNA表达无明显差异(P>0.05).结论 巴马司他通过降低MMP-9的浓度及活性,减轻细胞基底膜的降解,减轻肺 泡白细胞浸润和肺水肿,起到肺保护的作用.