基质金属蛋白酶-9与婴幼儿体外循环术后急性肺损伤的相关性

Relation between matrix Metallopreteinase-9 with acute lung injury in infants following cardiopulmonary bypass

目的探讨婴幼儿体外循环心内直视手术对外周血基质金属蛋白酶-9（MMP-9）及其组织抑制剂（TIMP-1）表达水平的影响及MMP-9、TIMP-1在术后急性肺损伤发生、发展中作用。方法随机选择24例房室水平左向右分流型先心病体外循环下行心内直视手术婴幼儿。ELISA法测定血浆MMP-9和TIMP-1水平,RT-PCR法测定外周血白细胞MMP-9mRNA的相对量,免疫荧光观察CPB前和CPB结束时白细胞内MMP-9含量的变化,同时测定CPB前、CPB结束时、CPB结束后1、3、6h肺泡-动脉氧分压差（AaDO2）、呼吸指数（RI）、氧合参数（OI）,分析MMP-9和MMP-9/TIMP-1比值与呼吸功能指标之间的相关性。结果（1）CPB后1、3、6、24h血浆MMP-9的水平与CPB前相比明显升高,差异具有统计学意义（P〈0.01）,其中CPB结束后3h血浆MMP-9浓度达到最高峰;（2）CPB后1、3、6、24h血浆TIMP-1的浓度与CPB前相比明显下降,差异具有统计学意义（P〈0.01）,其中CPB结束后3h血浆TIMP-1的浓度达到最低值;（3）CPB后1、3、6、24h血浆MMP-9/TIMP-1比值与CPB前相比明显升高,差异具有统计学意义（P〈0.01）,其中CPB结束后3h达到最大值;（4）CPB结束时、CPB结束后6、24h外周血白细胞MMP-9mRNA的相对量与CPB前相比明显增加,差异具有统计学意义（P〈0.01）;（5）CPB结束时、CPB后1、3、6hAaDO2、RI与CPB前相比明显升高,差异具有统计学意义（P〈0.01）,而OI与CPB前相比则明显下降,差异具有统计学意义（P〈0.01）。结论婴幼儿体外循环心直视手术后外周血MMP-9血浆水平和MMP-9mRNA转录水平明显增加,而血浆TIMP-1浓度明显下降,血浆MMP-9浓度和活性与婴幼儿体外循环心直视手术后急性肺损伤指标密切相关。外周血中MMP-9过度表达和MMP-9/TIMP-1比例失衡在婴儿体外循环手术后急性肺损伤形成过程中发挥重要作用。

Objective To investigate the effects of matrix metalloproteinase-9 （MMP-9） and matrix metalloproteinase inhibitor （TIMP-1） on the development of acute lung injury （ALl） after eardiopulmonary bypass （CPB） in infants. Method Systemic plasma concentrations of MMP-9 and TIMP-1 were measured by standard enzyme-linked immunosorbent assay （EI/SA） in randomly selected 24 infants suffered from left-to-right shunt congenital heart disease undergoing open heart operation along with CPB. MMP-9 mRNA within leukecytes was quantified by RT-PCR. Arterial-alveolar gradient of oxygen tension （AaDO2）, respiratory index （RI） and oxygen index （OI） were measured at pre-CPB, temaination of CPB, and 1, 3 and 6 hours after CPB. Correlation analysis was utilized to define the relationship between MMP-9 concentration and both the ratio of MMP-9/TIMP-1 as well as parameters of lung function （AaDO2, RI and OI ）. Results Plasma MMP-9 concentration significantly increased at 1, 3, 6 and 24 hours after CPB （ P 〈 0.01 ） compared with pre-CPB. Whereas plasma TIMP-1 concentration significantly decreased at 1, 3, 6 and 24 hours after CPB （ P 〈 0.01） compared with pre-CPB. The ratio of MMP-9/TIMP-1 significantly increased at 1, 3, 6 and 24 hours after CPB （ P 〈 0.01） compared with pre- CPB, and peaked at 3 hours after CPB. Level of MMP-9 mRNA within leukecytes significantly increased at temaination of CPB, and 6 and 24 hours after CPB （P 〈 0.01 ） compared with pre-CPB. AaDO2 and RI significantly increased after CPB （P〈0.01） compared with pre-CPB, whereas OI significantly decreased （P 〈 0.01）. Conclusions Plasma concentration of MMP-9 and mRNA content of MMP-9 teukocytesignificantly increase after cardiac surgery and CPB in infants, whereas plasma concentration of TIMP- 1 significantly decreases. The alteration of MMP-9 and TIMP-1 following CPB plays a role in the pathogenesis of ALl after CPB in infants.