基质金属蛋白酶-9和基质金属蛋白酶抑制剂-1在评估重症手足口病合并神经源性肺水肿的意义

Significance of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 levels in evaluation of severe hand, foot, and mouth disease complicated with neurogenie pulmonary edema

目的探讨血清和脑脊液中基质金属蛋白酶-9（matrix metalloproteinase-9, MMP-9）和基质金属蛋白酶抑制剂-1（tissue inhibitor of metalloproteinase-1, TIMP-1）在评估重症手足口病（hand，foot，and mouth disease，HFMD）合并神经源性肺水肿（neurogenic pulmonary edema，NPE）的临床意义。方法选取河南省儿童医院住院并确诊为HFMD的患儿140例，根据病情轻重程度分为轻症组、重症HFMD未合并NPE组、重症HFMD合并NPE组，并根据28 d预后生存率将重症HFMD患儿分为生存组及死亡组。同时选取50名同年龄段健康体检儿为对照组。所有入组儿童检测其血清中MMP-9、TIMP-1的水平，同时测重症HFMD未合并NPE组和重症HFMD合并NPE组患儿脑脊液中MMP-9、TIMP-1和MMP-9/TIMP-1比值。多种样本定量资料比较采用单因素方差分析，样本均数间的两两比较采用LSD-t检验。结果140例HFMD患儿中，其中轻症组66例，重症HFMD无NPE组42例，重症HFMD合并NPE组32例，健康对照组50名。28 d后重症HFMD患儿死亡14例。血清MMP-9、TIMP-1和MMP-9/TIMP-1比值在重症HFMD合并NPE组中明显升高，与其余3组比较差异均有统计学意义（F值分别为269.356、121.301和101.502，均P〈0.05）。重症HFMD合并NPE组患儿脑脊液MMP-9、TIMP-1和MMP-9/TIMP-1比值分别为（57.24±8.92） μg/L、（35.26±8.14） μg/L和1.66±0.23，重症HFMD无NPE组为（30.57±3.89） μg/L、（26.25±0.32） μg/L和1.17±0.61，两组比较差异均有统计学意义（t值分别为62.485、37.680和169.387，均P 〈0.01）。死亡组患儿MMP-9、TIMP-1和MMP-9/TIMP-1比值与生存组相比明显升高，差异均有统计学意义（均P〈0.01）。受试者工作特征曲线下面积最大为脑脊液MMP9/TIMP-1比值0.890（95%CI：0.801～0.978）。结论MMP-9和TIMP-1可能参与了重症HFMD合并NPE的发病过程，其检测有助于重症HFMD合并NPE的早期诊断。MMP-9/TIMP-1比值失衡可作为重症HFMD合并NPE的预测指标之一。

ObjectiveTo investigate the significance of matrix metalloproteinase-9 （MMP-9） and tissue inhibitor of metalloproteinase-1 （TIMP-1） in serum and cerebrospinal fluid for evaluation of severe hand, foot, and mouth disease （HFMD） complicated with neurogenic pulmonary edema （NPE）. MethodsA total of 140 patients diagnosed with HFMD in Henan Children′s Hospital were enrolled and divided into three groups including mild group, severe HFMD group without NPE , severe HFMD group with NPE .These severe HFMD patients were also divided into survival group and death group according to the 28-day prognosis. Meanwhile, 50 age-matched healthy children were selected as controls. Serum MMP-9 and TIMP-1 levels were measured in all enrolled children. At the same time, MMP-9, TIMP-1 and ratio of MMP-9/TIMP-1 in cerebrospinal fluid were measured in the severe HFMD group with and without NPE. Quantitative data were compared using one-way analysis of variance, and means comparisons between samples were conducted using LSD- t test.ResultsAmong 140 children with HFMD, 66 were in mild group, 42 in severe HFMD without NPE group, and 32 in severe HFMD with NPE group. And 50 healthy children were in control group. After 28 days, 14 cases died in severe HFMD groups. MMP-9, TIMP-1 and MMP-9/TIMP-1 in serum of severe HFMD group with NPE increased significantly greater than those in the other three groups （F=269.356, 121.301 and 101.502, respectively, all P 〈0.05）. MMP-9, TIMP-1 and MMP-9/TIMP-1 in cerebrospinal fluid of severe HFMD group with NPE were （57.24±8.92） μg/L, （35.26±8.14） μg/L and （1.66±0.23） μg/L, respectively, while those in cerebrospinal fluid of severe HFMD group without NPE were （30.57±3.89） μg/L, （26.25±0.32） μg/L and （1.17±0.61） μg/L, respectively. The differences between the two groups were all statistically significant （t=62.485, 37.680 and 169.387, respectively, all P〈0.01）. MMP-9, TIMP-1 and MMP-9/TIMP-1 in serum and cerebrospinal fluid of death group increased significantly greater than those in survival group, the difference were statistically significant （all P〈0.01）. The maximum area under curve （AUC） was reached when the MMP9/TIMP-1 ratio in cerebrospinal fluid was 0.890 （95% CI： 0.801-0.978）.ConclusionsMMP-9 and TIMP-1 may be involved in the pathogenesis of HFMD complicated with NPE. The detection of MMP-9 and TIMP-1 levels may be beneficial for the early diagnosis of severe HFMD with NPE. The imbalance of MMP-9/TIMP-1 ratio can be used as one of the predictors of severe HFMD combined with NPE.