克拉霉素通过抑制小鼠母胎炎症预防早产和降低新生小鼠死亡率的研究  

Clarithromycin prevents preterm birth and reduces neonatal mortality by suppressing maternal-fetal inflammation in mice

作　　者：王海燕[1] 黄守国[1] 蒙秋 张静[1] Wang Haiyan;Huang Shouguo;Meng Qiu;Zhang Jing(Department of Obstetrics and Gynecology,Haikou People’s Hospital,Haikou 570208,China)

机构地区：[1]海口市人民医院妇产科,海南海口570208

出　　处：《海军医学杂志》2023年第9期895-901,共7页Journal of Navy Medicine

基　　金：海口市重点学科妇科(2013-55);海南省2020年自然科学基金青年项目(820QN424);海南省2021年自然科学基金青年项目(821QN423)。

摘　　要：目的 本研究旨在探讨克拉霉素是否能通过抑制高迁移率族蛋白B1(high-mobility group box 1,HMGB1)的活性来减轻炎症反应,进而影响小鼠早产和不良新生小鼠结局。方法 采用HMGB1羊膜给药的方式诱导雌鼠(n=40)自发性早产和分娩,有3只雌鼠死亡。将给药后雌鼠随机分为实验组(n=19)和对照组(n=18)。实验组的雌鼠在HMGB1羊膜给药后接受皮下注射克拉霉素治疗,而对照组则接受等量的二甲基亚砜(dimethyl sulfoxide,DMSO)皮下注射。随后,对2组雌鼠的妊娠和新生小鼠结局进行了详细记录,收集雌鼠的羊水、胎盘、子宫蜕膜、子宫颈和胎儿组织,并进行炎症状态的生化检测。结果克拉霉素处理显著延长了实验组雌鼠的妊娠期,并降低早产率至7.13%(1/14),远低于对照组的46.15%(6/13)。此外,实验组有更高比例的新生小鼠能够存活至3周龄。生化检测结果显示,实验组雌鼠的子宫、子宫颈、胎膜和子宫蜕膜中多种炎症因子[如白细胞介素(interleukin,IL)-1α、IL-1β、干扰素-γ(interferon-γ,IFNG)等]的基因表达明显降低(P<0.05)。克拉霉素还能通过下调多个炎症和趋化因子基因[如IL-6、肿瘤坏死因子(tumor necrosis factor,TNF)、IL-12B、趋化因子配体(chemokine ligands,CCL)3、CCL5等]以及胎儿各组织(如肺、肠、肝和脾)中的炎症因子基因[如核因子-κB2(nuclear factor kappa B2,NF-κB2)、趋化因子CXCL9、Toll样受体4(toll-like receptor 4,TLR4)等]来提高新生小鼠的存活率(P<0.05)。结论 在HMGB1诱导的无菌性羊膜腔内炎症小鼠模型中,克拉霉素有效地抑制了子宫内母体组织(如子宫蜕膜和子宫颈)和胎儿的炎症反应,从而降低了早产率并改善了新生小鼠的结局。Objective To investigate whether clarithromycin can alleviate inflammation by inhibiting the activity of high-mobility group box 1(HMGB1),thereby affecting preterm birth and adverse neonatal outcomes in mice.Methods Spontaneous preterm birth and labor in mice were induced by HMGB1 amniotic administration.The female mice in the experimental group received subcutaneous injection of clarithromycin following HMGB1 amniotic administration,while the control group received an equal amount of dimethyl sulfoxide(DMSO) subcutaneously.Pregnancy and neonatal outcomes were then meticulously recorded for both groups.Additionally,amniotic fluid,placenta,decidua,cervix,and fetal tissues were collected for biochemical detection of inflammatory status.Results Clarithromycin treatment significantly extended the gestation period in the experimental group and reduced the preterm birth rate to 7.13%(1/14),far lower than 46.15%(6/13) in the control group.Moreover,a higher proportion of neonatal mice in the experimental group survived to three weeks of age.Biochemical assays revealed that the expression levels of various inflammatory factors such as Interleukin-1α(IL-1α),Interleukin-1β(IL-1β),and Interferon-γ(IFNG) were significantly reduced in the uterus,cervix,membranes,and decidua of the experimental group(P<0.05).Clarithromycin also improved the survival rate of neonatal mice by downregulating multiple inflammatory and chemotactic factor genes [e.g.,Interleukin-6(IL-6),tumor necrosis factor(TNF),interleukin-12B(IL-12B),and chemokine ligands(CCL)3,CCL5] as well as inflammatory genes [e.g.,nuclear factor kappa B2(NF-κB2),chemokine CXCL9,toll-like receptor 4(TLR4)] in fetal tissues(e.g.,lung,intestine,liver and spleen)(P<0.05).Conclusion In a mouse model of sterile amniotic cavity inflammation induced by HMGB1,clarithromycin effectively suppressed the inflammatory response in maternal tissues(e.g.,decidua and cervix) and the fetus in the uterus,thereby reducing the preterm birth rate and improving outcomes in neonatal mice.

关 键 词：克拉霉素 警报素 高迁移率族蛋白B1 早产 炎症 

分 类 号：R339.2[医药卫生—人体生理学]