外周血 MMP-9/TIMP-1、ox-AAT 及 miR-200对胎膜早破并发绒毛膜羊膜炎的预测价值

Predictive value of MMP-9/TIMP-1, ox-AAT and miR-200 in peripheral blood for premature rupture of membranes complicated by chorioamnionitis

摘要

目的 分析外周血基质金属蛋白酶-9(MMP-9)/基质金属蛋白酶抑制因子-1(TIMP-1)、氧化型α₁-抗胰蛋白酶(ox-AAT)及微小核糖核酸-200(miR-200)对胎膜早破(PROM)并发绒毛膜羊膜炎(CAM)的预测价值。方法 选取2021年5月至2024年5月海口市妇幼保健院收治的506例PROM患者为研究对象,根据PROM患者是否并发CAM分为CAM组(n=124)和对照组(n=382),CAM组根据CAM分期分为Ⅰ期组(n=59)和Ⅱ~Ⅲ期组(n=65)。比较CAM组和对照组、Ⅰ期组和Ⅱ~Ⅲ期组外周血MMP-9/TIMP-1、ox-AAT、miR-200水平,比较CAM组和对照组临床资料;Spearman法分析PROM患者外周血MMP-9/TIMP-1、ox-AAT、miR-200水平与CAM分期的相关性;多因素Logistic回归分析影响PROM患者并发CAM的因素;受试者工作特征(ROC)曲线分析MMP-9/TIMP-1、ox-AAT、miR-200对PROM患者并发CAM的预测价值。结果 CAM组外周血MMP-9/TIMP-1、ox-AAT、miR-200水平高于对照组(t值分别为14.443、11.189、12.362,P<0.001)。Ⅱ~Ⅲ期组MMP-9/TIMP-1、ox-AAT、miR-200水平高于Ⅰ期组(t值分别为10.489、9.492、5.424,P<0.001)。Spearman相关性分析显示,MMP-9/TIMP-1、ox-AAT、miR-200与CAM分期呈正相关(r值分别为0.689、0.657、0.426,P<0.001)。Logistic回归结果显示,下生殖道感染、白细胞计数(WBC)、C反应蛋白(CRP)、中性粒细胞(NE)、降钙素原(PCT)、MMP-9/TIMP-1、ox-AAT、miR-200是PROM患者并发CAM的影响因素(OR介于2.375到4.125之间,P<0.05)。MMP-9/TIMP-1、ox-AAT、miR-200联合检测预测PROM患者并发CAM的曲线下面积(AUC)为0.947(95%CI:0.925~0.968)、灵敏度91.1%、特异度为87.7%,优于MMP-9/TIMP-1、ox-AAT、miR-200单独检测(Z值分别为2.234、2.561、2.418,P<0.05)。结论 MMP-9/TIMP-1、ox-AAT、miR-200在PROM患者并发CAM中具有良好的预测价值。

Abstract

Objective To analyze the predictive value of peripheral blood matrix metalloproteinase-9 (MMP-9)/tissue inhibitor of metalloproteinases-1 (TIMP-1), oxidized α₁-antitrypsin (ox-AAT) and microribonucleic acid-200 (miR-200) in premature rupture of membranes (PROM) complicated by chorioamnionitis (CAM). Methods A total of 506 PROM patients admitted to Haikou Maternal and Child Health Hospital from May 2021 to May 2024 were selected as the study subjects, and the PROM patients were divided into CAM group (n=124) and control group (n=382) according to whether they had CAM concurrent with CAM, and the CAM group was divided into stage Ⅰ group (n=59) and stage Ⅱ-Ⅲ group (n=65) according to CAM stage. The levels of MMP-9/TIMP-1, ox-AAT, and miR-200 in peripheral blood of CAM group and control group, stage Ⅰ group and stage Ⅱ-Ⅲ group were compared, and the clinical data of CAM group and control group were compared. The Spearman method was used to analyze the correlation between the levels of MMP-9/TIMP-1, ox-AAT, miR-200 and CAM stage in the peripheral blood of PROM patients. Multivariate logistic regression analysis was performed to analyze the factors affecting the concurrent CAM of PROM patients. The receiver operating characteristic (ROC) curve was used to analyze the predictive value of MMP-9/TIMP-1, ox-AAT, and miR-200 on the concurrent CAM of PROM patients. Results The levels of MMP-9/TIMP-1, ox-AAT, and miR-200 in the CAM group were higher than those in the control group (t-values were 14.443, 11.189, and 12.362, respectively, P<0.001). The levels of MMP-9/TIMP-1, ox-AAT, and miR-200 in stage Ⅱ-Ⅲ group were higher than those in stage Ⅰ group (t-values were 10.489, 9.492, and 5.424, respectively, P<0.001). Spearman correlation analysis showed that MMP-9/TIMP-1, ox-AAT, and miR-200 were positively correlated with CAM stage (r values were 0.689, 0.657, 0.426, P<0.001, respectively). Logistic regression results showed that lower genital tract infection, white blood cell count (WBC), C-reactive protein (CRP), neutrophils (NE), procalcitonin (PCT), MMP-9/TIMP-1, ox-AAT, and miR-200 were the influencing factors of CAM in patients with PROM (OR ranged from 2.375 to 4.125, P<0.05). The area under the curve (AUC) of MMP-9/TIMP-1, ox-AAT, and miR-200 in predicting the concurrent CAM of patients with PROM was 0.947 (95%CI: 0.925-0.968), the sensitivity was 91.1%, and the specificity was 87.7%, which was better than that of MMP-9/TIMP-1, ox-AAT, and miR-200 alone (Z-values were 2.234, 2.561, 2.418, P<0.05, respectively). Conclusion MMP-9/TIMP-1, ox-AAT, and miR-200 have good predictive value in the concurrent CAM of PROM patients.

关键词

胎膜早破 / 绒毛膜羊膜炎 / 基质金属蛋白酶-9 / 基质金属蛋白酶抑制因子-1 / 氧化型α ₁-抗胰蛋白酶 / 微小核糖核酸-200

Key words

premature rupture of membranes / chorioamnionitis / matrix metalloproteinase-9 / tissue inhibitor of metalloproteinases-1 / oxidized α ₁-antitrypsin / microRNA-200

参考文献

[1] Garg A, Jaiswal A. Evaluation and management of premature rupture of membranes: a review article[J]. Cureus, 2023, 24; 15(3): e36615.

[2] Balciuniene G, Gulbiniene V, Dumalakiene I, et al. Prognostic markers for chorioamnionitis: IL-6, TNF-α, and MMP-8 in vaginally obtained amniotic fluid[J]. J Clin Med, 2021, 10(5): 1136.

[3] Jung E, Romero R, Suksai M, et al. Clinical chorioamnionitis at term: definition, pathogenesis, microbiology, diagnosis, and treatment[J]. Am J Obstet Gynecol, 2024, 230(3S): S807-S840.

[4] 姜燕, 任荣, 叶晖. 脐血中sTREM-1、pro-ADM水平对胎膜早破早产儿早发型细菌感染的预测作用[J]. 中国妇幼健康研究, 2022, 33(4): 51-55.

[5] Nguyen L M, Aronoff D M, Eastman A J. Matrix metalloproteinases in preterm prelabor rupture of membranes in the setting of chorioamnionitis: a scoping review[J]. Am J Reprod Immunol, 2023, 89(1): e13642.

[6] Rashid Z A, Bardaweel S K. Novel matrix metalloproteinase-9 (MMP-9) inhibitors in cancer treatment[J]. Int J Mol Sci, 2023, 24(15): 12133.

[7] Cabral-Pacheco G A, Garza-Veloz I, Castruita-De la Rosa C, et al. The roles of matrix metalloproteinases and their inhibitors in human diseases[J]. Int J Mol Sci, 2020, 21(24): 9739.

[8] 张莉敏, 王铁锋, 梁盼盼, 等. 脐血sCD14、sTREM-1、IL-6、ox-AAT及NE与胎膜早破并发绒毛膜羊膜炎、新生儿肺炎的关系[J]. 实用预防医学, 2022, 29(12): 1515-1517.

[9] Tsuda S, Shinagawa T, Tsumura K, et al. Estimated time to emergence of secondary intra-amniotic infection or inflammation since the onset of the preterm premature rupture of membranes[J]. J Obstet Gynecol, 2022, 61(4): 634-640.

[10] Gomez-Lopez N, Romero R, Varrey A, et al. RNA sequencing reveals diverse functions of amniotic fluid neutrophils and monocytes/macrophages in intra-amniotic infection[J]. J Innate Immun, 2021, 13(2): 63-82.

[11] 中华医学会妇产科学分会产科学组. 胎膜早破的诊断与处理指南(2015)[J]. 中华围产医学杂志, 2015, 18(3): 161-167.

[12] 郭孝, 谢诺, 王雪姣, 等. 胎膜早破孕妇生殖道感染病原菌特征及抗生素治疗效果分析[J]. 中国病原生物学杂志, 2024, 19(2): 187-190, 195.

[13] Jain V G, Willis K A, Jobe A, et al. Chorioamnionitis and neonatal outcomes[J]. Pediatr Res, 2022, 91(2): 289-296.

[14] Feduniw S, Pruc M, Ciebiera M, et al. Biomarkers for pregnancy latency prediction after preterm premature rupture of membranes-a systematic review[J]. Int J Mol Sci, 2023, 24(9): 8027.

[15] 韩艳茹, 刘敏, 王俊鹏, 等. 胎膜早破患者宫颈分泌液MMP-9、MCP-1、GRO-α与生殖道感染的关系[J]. 中华医院感染学杂志, 2022, 32(22): 3467-3471.

[16] 吴慧, 韩文龙, 柏蕾, 等. 胎膜早破产妇血清SFRP5,TIMP-1和HMGB1水平与并发组织学绒毛膜羊膜炎的相关性研究[J]. 现代检验医学杂志, 2022, 37(5): 112-117, 158.

[17] 史晓玲, 马小云, 拜翠莲. 手足口病合并脑炎患儿血清和脑脊液中MMP-9和TIMP-1水平的临床价值分析[J]. 中国妇幼健康研究, 2023, 34(5): 16-24.

[18] 高静, 张家宽, 邢书琴, 等. 硝苯地平联合盐酸利托君治疗早产胎膜早破患者的疗效及其对外周血炎症细胞因子的影响[J]. 广西医学, 2024, 46(4): 519-523.

[19] Li H L, Fan J F, Fan L Y, et al. Erratum to “MiRNA-10b reciprocally stimulates osteogenesis and inhibits adipogenesis partly through the TGF-β/SMAD2 signaling pathway”[J]. Aging Dis, 2021, 12(7): 1543-1544.

[20] Rashid M, Devi B M, Banerjee M. Combinatorial cooperativity in miR200-Zeb feedback network can control epithelial-mesenchymal transition[J]. Bull Math Biol, 2024, 86(5): 48.

[21] 李顺序, 刘玲艳, 李毅. 外周血miR-200对未足月胎膜早破合并羊膜腔感染的预测价值分析[J]. 中国妇产科临床杂志, 2022, 23(3): 291-292.

基金资助

海南省自然科学基金面上项目(821MS0847)