胎膜早破发病机制的研究进展

胎膜早破(premature rupture of fetal membranes,PROM)是产科临床非常普遍且相当棘手的问题,是早产的常见原因,若不能合理处理,母儿的生命就会受到威胁。引起胎膜早破的原因众多,其发病机制也十分复杂。综述胎膜破口区域的组织学特征,包括传统病理学和新型光学研究观察结果;其次介绍新发现的胎膜存在微小裂隙并持续重塑的观点;另外部分早破胎膜破口有发生自发性愈合,总结胎膜破口自愈现象的机制,主要是以细胞迁移为基础的物理性封闭;PROM发生机制一直以来都是研究热点,介绍当下较新的理论如胎膜老化和胎膜氧化应激失衡研究进展,同时对胎膜细胞凋亡、胎膜蛋白酶系统/抗蛋白酶系统平衡失调等传统理论的新近研究加以综述,旨在为胎膜早破进一步研究提供理论思路。     

IL-1β、MMP-8和胎儿胸腺等预测胎膜早破合并绒毛膜羊膜炎的研究进展

胎膜早破(premature rupture of membrane,PROM)常发生于妊娠中晚期。胎膜破裂后,阴道内的致病微生物可沿胎膜破口进入羊膜腔,可诱发绒毛膜羊膜炎(chorioamnionitis,CA),导致胎儿窘迫和新生儿感染败血症等严重并发症的发生,是临床围生儿病死率升高的重要原因。大多数患者在胎膜早破后短期内没有临床症状,但早期预警并给予相应处理可明显降低围生儿患病率和死亡率,如孕晚期B型溶血性链球菌筛查及相应的治疗。近年研究发现,除传统的实验室预测指标如白细胞介素6(IL-6)外,IL-1β、基质金属蛋白酶8(MMP-8)和胎儿胸腺的超声测量等对CA具有一定的预测价值。综述近年来PROM并发CA早期预测指标的研究进展。     

IL-1β、MMP-8和胎儿胸腺等预测胎膜早破合并绒毛膜羊膜炎的研究进展

胎膜早破（premature rupture of membrane，PROM）常发生于妊娠中晚期。胎膜破裂后，阴道内的致病微生物可沿胎膜破口进入羊膜腔，可诱发绒毛膜羊膜炎（chorioamnionitis，CA），导致胎儿窘迫和新生儿感染败血症等严重并发症的发生，是临床围生儿病死率升高的重要原因。大多数患者在胎膜早破后短期内没有临床症状，但早期预警并给予相应处理可明显降低围生儿患病率和死亡率，如孕晚期B型溶血性链球菌筛查及相应的治疗。近年研究发现，除传统的实验室预测指标如白细胞介素6（IL-6）外，IL-1β、基质金属蛋白酶8（MMP-8）和胎儿胸腺的超声测量等对CA具有一定的预测价值。综述近年来PROM并发CA早期预测指标的研究进展。     

MMPs/TIMPs与胎膜早破关系的研究

胎膜早破(PROM)的病因至今未明,近年研究多集中于胎膜胶原代谢方面,这一代谢主要依赖于基质金属蛋白酶(MMPs)的作用,可降解胎膜中的细胞外基质,其活性受特异性的金属蛋白酶组织抑制剂(TIMPs)的抑制.通过研究羊水、血清和胎膜中MMPs、TIMPs变化,多数认为MMPs/TIMPs平衡失调是PROM发生的重要原因.     

间隙连接蛋白43与胎膜早破的相关性

胎膜早破（premature rupture of membranes,PROM）是产科最常见的早产原因之一,可诱发新生儿呼吸窘迫综合征、绒毛膜羊膜炎、胎盘早剥、败血症等不良结局。间隙连接通讯是细胞间最常见的信息交互及物质交换途径,其功能主要由间隙连接蛋白实现,间隙连接蛋白43（Connexin43,Cx43）是间隙连接蛋白家族中最常见且最重要的一类间隙连接蛋白,Cx43的半通道结构可在细胞间进行连接,形成细胞间的完整传输通道,在细胞间缝隙连接、细胞间信息和物质交流及胎膜完整性中发挥重要作用,Cx43在胎膜中的表达与胎膜中Ⅰ、Ⅲ型胶原表达水平有密切关系,并可通过影响Ⅰ、Ⅲ型胶原数量及交联方式而致胎膜薄弱,进而导致胎膜早破。Cx43降低可致胎膜微裂隙发生及扩大进而导致胎膜早破发生,本文就Cx43与胎膜早破的相关性进行综述,以期对胎膜早破的发生机制及防治有进一步认识。     

MMPs／TIMPs与胎膜早破关系的研究

胎膜早破(PROM)的病因至今未明，近年研究多集中于胎膜胶原代谢方面，这一代谢主要依赖于基质金属蛋白酶(MMP3)的作用，可降解胎膜中的细胞外基质，其活性受特异性的金属蛋白酶组织抑制剂(TIMPs)的抑制。通过研究羊水、血清和胎膜中MMP3、TIMPs变化，多数认为MMPs／TIMP3平衡失调是PROM发生的重要原因。     

生物学途径协同作用与胎膜早破的研究进展

胎膜早破（PROM）是围生期胎儿发病率和死亡率增加的一个危险因素。现有资料及医学技术仍难以精准预测胎膜早破的发生,了解PROM的发生机制,准确及时诊断PROM对减少母婴感染至关重要。研究发现,细胞因子、凝血酶和基质金属蛋白酶激活、氧化应激和凋亡是PROM发生的主要生物学途径。而这些生物过程是由包括感染、炎症、胎盘出血和子宫过度膨胀在内的多种病因引起的,将各个生物学途径的协同作用与胎膜的弱化联系起来探讨PROM的生物学发生机制,从生物学角度对胎膜早破的预测和防治找到突破口,对现代医学意义重大。     

Cx43、Bax和Bcl-2在胎膜早破患者胎膜组织中的表达及意义

目的检测间隙连接蛋白43（Cx43）在胎膜早破患者胎膜组织中的表达,分析其与凋亡相关蛋白Bax、Bcl-2表达的相关性,探讨三者与胎膜早破发生的关系。方法随机选择本院剖宫产分娩的孕32-42周胎膜早破孕妇30例（胎膜早破组）,其中未足月胎膜早破（pPROM）15例,足月胎膜早破（tPROM）15例;无胎膜早破孕妇30例（对照组）。采用免疫组化法（PV法）检测Cx43、Bax和Bcl-2的表达并进行图像分析。结果①各组胎膜组织中均可见Cx43、Bax、Bcl-2不同程度的表达。②tPROM组Cx43、Bcl-2的表达明显低于对照组（P〈0．01）,而Bax的表达高于对照组,差异均有显著性（P〈0．05）。tPROM组Cx43的表达高于pPROM组,差异有显著性（P〈0．01）;而Bcl-2、Bax在两组中比较,差异无显著性（P〉0．05）。③PROM组人工胎膜破口附近Cx43、Bcl-2的表达低于非人工胎膜破口附近,Bax的表达则相反,两组比较,差异有显著性（均P〈0．01）。④PROM组Cx43的表达水平与Bax呈负相关（r=-0．309,P〈0．05）。结论胎膜组织中Cx43的低表达及细胞的过度凋亡可能对胎膜早破的发生起一定的促进作用。     

生物学途径协同作用与胎膜早破的研究进展

胎膜早破(PROM)是围生期胎儿发病率和死亡率增加的一个危险因素。现有资料及医学技术仍难以精准预测胎膜早破的发生,了解PROM的发生机制,准确及时诊断PROM对减少母婴感染至关重要。研究发现,细胞因子、凝血酶和基质金属蛋白酶激活、氧化应激和凋亡是PROM发生的主要生物学途径。而这些生物过程是由包括感染、炎症、胎盘出血和子宫过度膨胀在内的多种病因引起的,将各个生物学途径的协同作用与胎膜的弱化联系起来探讨PROM的生物学发生机制,从生物学角度对胎膜早破的预测和防治找到突破口,对现代医学意义重大。     

Ets-1和MMP-9在胎膜早破中的表达

目的研究转录因子Ets-1和基质金属蛋白酶-9（MMP-9）在胎膜早破中的表达和作用。方法胎膜早破（PROM）患者67例,胎膜未破裂组70例,分娩后取破口处胎膜组织,采用免疫组织化学法染色,并使用病理影像多媒体图文操作系统对Ets-1和MMP-9阳性表达物的面积积分光密度（AIOD）进行半定量分析。结果①Ets-1在胎膜滋养层细胞核及胞浆中均有表达,且细胞核表达明显;MMP-9在胎膜滋养层细胞中的表达,主要位于细胞浆中;②Ets-1在胎膜早破组（0.0373±0.0119）中高表达,与胎膜未破裂组（0.0062±0.0089）比较,差异有高度统计学意义（P〈0.001）;③MMP-9在胎膜早破组（0.0928±0.0453）中高表达,与胎膜未破裂组（0.0345±0.039）比较,差异有高度统计学意义（P〈0.001）。结论Ets-1和MMP-9在人类胎膜上均有表达,且在胎膜早破中高表达且具显著相关性,表明Ets-1可能通过上调MMP-9的基因表达量使胎膜细胞外基质（ECM）的降解加速致胎膜紧张度降低,引发胎膜早破。     

Is the collagen content reduced when the fetal membranes rupture? A clinical study of term and prematurely ruptured membranes

In 15 patients experiencing premature rupture of the fetal membranes (PROM) and in 15 control subjects having delivered spontaneously at term, the collagen content of the membranes was determined by the hydroxyproline method. From each patient two membrane specimens were obtained, one from the rupture margin and another from the membranes in close relation to the placental margin. No significant difference in the collagen content was demonstrated between the two groups of patients. Moreover, no significant difference was observed comparing the collagen content within the paired membrane specimens of each patient in each group. Neither was there any obvious change in the membrane collagen content in relation to clinical signs of chorioamnionitis or microbiological findings. It is concluded that changes in the collagen content of the fetal membranes bear no significance as to the etiology of PROM, neither is such a change involved in the mechanism of membrane rupture at term.     

Role of apoptosis,bcl-2 and bax protein expression in premature rupture of fetal membranes

OBJECTIVE: To examine the degree of apoptosis in human fetal membranes associated with premature rupture of membranes (PROM) as compared with normal pregnancies and to evaluate the expression of proapoptotic bax and antiapoptotic bcl-2 gene products. STUDY DESIGN: Fetal membranes from 50 pregnancies were included in the study. Thirty of 50 pregnancies had PROM. Twenty pregnancies with intact membranes served as controls. Chorioamniotic membrane biopsies were taken from the rupture site of the membrane and periphery of the rupture side. In the control group, membrane biopsies were taken from the artificial rupture site, cervical pole of the membranes and membranes close to the edge of the placenta. In recognizing apoptotic figures, routinely processed samples were stained with hematoxylin and eosin for light microscopic evaluation. Quantification of the apoptotic cells was performed with high-power fields and expressed as the number per 100 cells. The membranes of both groups were then stained with bcl-2 and bax antibodies by using the standard steptavidin-biotin-immunoperoxidase method. Staining with both antibodies were compared between two groups. RESULTS: Apoptotic cells were detected in the amniotic epithelium, in chorionic cells and fibroblastic layer of the fetal membranes. Apoptotic cells were found mostly in the chorionic cells. There was a statistically significant difference between the apoptotic index in PROM and the control group in both rupture and peripheral sites (P < .05), although within each group peripheral and rupture sites showed no difference in terms of apoptotic cell counts. Both bax and bcl-2 expression was observed in 40% of control cases and in 57% and 50% of cases with PROM, respectively, mostly in the chorionic trophoblastic cells. The PROM and control groups showed no statistically significant difference in terms of bcl-2 and bax protein expression. CONCLUSION: Apoptosis may play a role in the pathogenesis of PROM, but the changes in apoptosis do not seem to be mediated by bcl-2 and bax genes in the amniotic membrane. Other regulatory mechanisms must be investigated.     

Caspase-8及Bcl-2表达与胎膜早破的相关性研究

目的:探讨Caspase-8及Bcl-2表达与胎膜早破的关系。方法:选择2003年6月~2004年5月我院足月妊娠自然分娩的孕妇48例,其中24例发生胎膜早破(胎膜早破组),24例未发生胎膜早破(对照组),病例均于阴道分娩后取胎膜破裂口处的胎膜组织5cm×5cm大,同时胎膜早破组在距胎膜破口处10cm以上的部位再取同样大的胎膜组织,胎膜组织均经石蜡包埋切片后采用免疫组化法测定Caspase-8及Bcl-2的表达。结果:(1)两组病例的胎膜组织均可见Caspase-8及Bcl-2的表达;(2)在胎膜早破组的胎膜组织中Caspase-8表达的阳性单位为6.89±0.19,对照组为2.33±0.06(P<0.01);而Bcl-2表达的阳性单位为9.55±0.24,对照组为21.37±0.32(P<0.01);(3)在胎膜早破组非破口部位胎膜组织中Caspase-8及Bcl-2表达的阳性单位分别为6.93±0.17和9·66±0.19,与破口部位胎膜组织中Caspase-8及Bcl-2表达的阳性单位比较无差异(P>0·05)。结论:胎膜早破的发生与Caspase-8的过度表达及Bcl-2表达的下调相关。     

Preterm prelabor rupture of the membranes: A disease of the fetal membranes

Preterm prelabor rupture of the membranes (pPROM) remains a significant obstetric problem that affects 3–4% of all pregnancies and precedes 40–50% of all preterm births. pPROM arises from complex, multifaceted pathways. In this review, we summarize some old concepts and introduce some novel theories related to pPROM pathophysiology. Specifically, we introduce the concept that pPROM is a disease of the fetal membranes where inflammation–oxidative stress axis plays a major role in producing pathways that can lead to membrane weakening through a variety of processes. In addition, we report microfractures in fetal membranes that are likely sites of tissue remodeling during gestation; however, increase in number and morphometry (width and depth) of these microfractures in pPROM membranes suggests reduced remodeling capacity of membranes. Microfractures can act as channels for amniotic fluid leak, and inflammatory cell and microbial migration. Further studies on senescence activation and microfracture formation and their role in maintaining membrane homeostasis are needed to fill the knowledge gaps in our understanding of pPROM as well as provide better screening (biomarker and imaging based) tools for predicting women at high risk for pPROM and subsequent preterm birth.     

细胞凋亡与胎膜早破的相关性研究

目的:探讨细胞凋亡增加是否为胎膜早破的一个发病机理或危险因素。方法:随机采集临产前剖宫产分娩的初产妇肘静脉血、羊水及胎膜,其中胎膜早破者34例,正常完好胎膜17例。①用ELISA测定各组血清、羊水中TNF-α的浓度:②用TUNEL原位标记术精确测定各组胎膜细胞凋亡指数;③用免疫组化法检测各组胎膜组织中Bax、Bcl-2、Fas、Caspase-3表达情况。结果:①胎膜早破组血清、羊水中TNF-α浓度明显高于正常对照组水平(P<0.001);且血清、羊水中TNF-α浓度有相关性,r=0.386。胎膜感染组血清、羊水中TNF-α浓度较无感染组高(P<0.001)。②胎膜早破组胎膜感染发生率高于对照组(P<0.05)。③胎膜早破组细胞凋亡指数明显高于正常组(P<0.001);感染组细胞凋亡指数较无感染组高(P<0.001)。④胎膜早破组促凋亡蛋白Bax、Fas、Caspase-3阳性表达率高于对照组(P<0.05),但抑凋亡蛋白Bcl-2阳性表达率两组间无统计学差异(P>0.05);胎膜感染组Bax、Bcl-2、Caspase-3阳性表达率与无感染组比较无统计学差异(P>0.05),但感染组Fas阳性表达率高于无感染组(P<0.05)。结论:基因、环境因素相互作用下的细胞凋亡增加可能是胎膜早破的一个重要发病机制,可独立致病,亦或与其他相关危险因素(如感染)协同致病。     

胎膜组织BMP-2及MMP-9的表达及与胎膜早破的关系

目的:探讨胎膜组织骨形成蛋白-2(BNP-2)及基质金属蛋白酶-9(MMP-9)与胎膜早破(PROM)发生的关系.方法:选择足月临产产妇、足月PROM产妇、早产临产产妇、早产PROM产妇及足月未临产产妇(对照组)各18例,分娩后取破口处胎膜组织,采用免疫组织化学法染色,并使用病理影像多媒体图文操作系统对BMP-2、MMP-9阳性表达物的面积积分光密度(AIOD)进行半定量分析.结果:①胎膜组织中BMP-2和MMP-9阳性表达的AIOD在足月临产组、足月PRON组、早产临产组、早产PROM组均高于对照组,差异均有统计学意义(P<0.0071);②足月PROM组BMP-2和MMP-9高于足月临产组(P=0.0065,P=0.0069);早产PROM组BNP-2和NMP-9高于早产临产组(P=0.0069,P=0.0052);早产PROM组BMP-2和MMP-9高于足月PROM组(P=0.0037,P=0.0065);③5组胎膜组织中BMP-2和MMP-9的表达均呈明显正相关(r_s=0.76159,P<0.0001).结论:BMP-2和MMP-9与胎膜破裂的发生密切相关,胎膜组织中BMP-2与MMP-9的表达水平相关.     

Association of type II apoptosis and 92-kDa type IV collagenase expression in human amniochorion in prematurely ruptured membranes with tumor necrosis factor receptor-1 expression

OBJECTIVE: We assessed the presence of tumor necrosis factor receptor-1 (TNF-R1), apoptosis, and simultaneous expression of 92-kDa collagenase type IV (MMP-9) in samples of human chorioamnion from women with premature rupture of membranes (PROM). METHODS: Amniotic membranes from women who underwent normal labor, cesarean delivery, or had PROM at term were studied by immunohistochemistry for localization of TNF-R1 and R2. Transmission electron microscopy and DNA fragmentation analyses by agarose gel electrophoresis were performed to identify apoptosis characteristics. Zymography and in situ zymography were used to assess gelatinolytic activity. RESULTS: We found that TNF-R1 was abundant in membranes from subjects who had normal labor and very abundant in those who had PROM. By contrast TNF-R2 was abundant only in membranes from subjects who had cesarean delivery. Gelatinolytic activity was associated with extracellular matrix rather than cells and was higher in extracts from fetal membranes from PROM and normal labor than in extracts obtained from cesarean deliveries. Transmission electron microscopy of fetal membranes from PROM revealed ultrastructural characteristics in amnion epithelium consistent with type II apoptosis. DNA laddering in agarose gel electrophoresis corroborated results from DNA fragmentation. CONCLUSION: During PROM the fetal membranes undergo type II apoptosis and extracellular matrix degradation in association with TNF-R1 expression.