MMP-9、TIMP-1水平变化参与FIRS早产儿心肌损伤的机制研究  

Study on the mechanism by which MMP-9 and TIMP-1 levels are involved in myocardial injury in premature infants with FIRS

作　　者：闫祎炜 江莲[1] 李梅[1] 张文浩 张文婷[1] 王晓玲[2] 张原苏 张会芬[1] YAN Yiwei;JIANG Lian;LI Mei;ZHANG Wenhao;ZHANG Wenting;WANG Xiaoling;ZHANG Yuansu;ZHANG Huifen(Department of Pediatrics,the Fourth Hospital of Hebei Medical University,Shijiazhuang 050000,China;Department of Pathology,the Fourth Hospital of Hebei Medical University,Shijiazhuang 050000)

机构地区：[1]河北医科大学第四医院儿科,石家庄050000 [2]河北医科大学第四医院病理科,石家庄050000

出　　处：《中国比较医学杂志》2022年第6期55-61,共7页Chinese Journal of Comparative Medicine

基　　金：2017年河北省政府资助临床医学优秀人才培养和基础课题研究项目(冀财社[2017]46号);2016年河北省医学科学研究重点课题计划(20160163)。

摘　　要：目的通过临床研究及构建小鼠胎儿炎症反应综合征(fetal inflammatory response syndrome,FIRS)模型,探究早产儿FIRS体内MMP-9/TIMP-1表达水平变化参与FIRS引发心肌损害的可能机制及其潜在药物的发掘。方法本研究分为临床观察和动物实验两部分。临床部分:纳入2018年5月至2019年12月于河北医科大学第四医院生产的全部早产儿118例作为研究对象,根据是否诊断FIRS分为FIRS组(n=61)和非FIRS组(n=57),比较两组患儿IL-6、MMP-9、TIMP-1、MMP-9/TIMP-1(M/T)比值水平及心肌损伤发生情况。动物部分:构建FIRS小鼠模型,根据不同药物干预方式,分为FIRS组、RA组、对照组,留取3组小鼠心脏及胎盘组织,观察心脏及胎盘组织病理改变及心脏组织中IL-6、MMP-9、TIMP-1、MMP-9/TIMP-1(M/T)比值水平变化。结果临床部分:FIRS组IL-6、MMP-9、TIMP-1及M/T比值分别为(38.53±9.01)pg/L、(42.27±12.53)ng/L、(110.48±17.06)ng/L、(38.30±9.93)%,显著高于非FIRS组,差异具有统计学意义(P<0.05);FIRS组心肌损伤率(27.87%)显著高于非FIRS组(5.26%),差异具有统计学意义(P=0.001)。动物部分:FIRS组小鼠心肌组织明显水肿、心室壁变薄,RA干预后心脏结构变化程度减轻。不同时间点FIRS组小鼠IL-6、MMP-9、TIMP-1 mRNA表达量及M/T比值显著高于对照组(P<0.05);RA干预后,相同时间节点IL-6、MMP-9 mRNA表达量及M/T比值显著高于对照组(P<0.05),但是低于FIRS组(P<0.05)。结论FIRS可通过释放IL-6,调节MMP-9、TIMP-1及M/T比值水平,介导早产儿心肌损伤的发生,应用MMP-9抑制类药物可在心肌损伤过程中发挥保护作用,为发掘临床潜在治疗药物提供线索。Objective To explore,by constructing a mouse fetal inflammatory response syndrome(FIRS)model,the possible mechanism by which MMP-9/TIMP-1 expression in premature infants with FIRS induces myocardial damage and potential drugs against this.Methods This study was divided into two parts:clinical observation and animal experiment.In part 1,a total of 118 premature infants who were in the Fourth Hospital of Hebei Medical University during the period from May 2018 to December 2019 were included as the study participants.According to whether FIRS was diagnosed,they were divided into the FIRS group(n=61)and control group(n=57).The levels of IL-6,MMP-9 and TIMP-1,the MMP-9/TIMP-1(M/T)ratio,and the occurrence of myocardial injury were compared between the two groups.For part 2(the animal experiment),FIRS mice were constructed and divided into the following three drug intervention groups:FIRS group,RA(retinoic acid)group,and control group.Heart tissue was collected from the mice in these groups and used to detect the IL-6,MMP-9 and TIMP-1 levels and the M/T ratio.Results The IL-6,MMP-9 and TIMP-1 levels and M/T ratio in the FIRS group were:(38.53±9.01)pg/L,(42.27±12.53)ng/L,(110.48±17.06)ng/L and(38.30±9.93)%,respectively;these values were significantly higher(P<0.05)than those in the non-FIRS group.The myocardial injury rate was significantly higher(P=0.001)in the FIRS group(27.87%)than in the non-FIRS group(5.26%).In the myocardial tissue of mice in the FIRS group,there were significant levels of edema,the ventricular wall became thinner,and the degree of cardiac structure changes was reduced by RA intervention.The IL-6,MMP-9 and TIMP-1 mRNA expression levels and M/T ratios in the FIRS group at different timepoints were significantly higher than those in the control group(P<0.05),whereas the the mRNA expression of IL-6,MMP-9 levels and M/T ratios in the RA group were significantly higher than those in the control group(P<0.05)but were lower than those in the FIRS group(P<0.05).Conclusions FIRS can mediate the occurren

关 键 词：胎儿炎症反应综合征 心肌损伤 金属基质蛋白酶-9 金属蛋白酶组织抑制因子-1 白介素-6 

分 类 号：R-33[医药卫生]