摘要
目的
研究宫缩乏力性产后出血产妇子宫平滑肌自发性收缩功能和收缩潜能的变化,及其子宫平滑肌组织中丝裂原激活蛋白激酶(mitogen-activated protein kinase ,MAPK)信号转导通路中细胞外信号调节激酶(extracellular-signal regulated kinase1,ERK1/2)、c-Jun N端蛋白激酶(c-jun N-terminal kinase,JNK1/2)和p38蛋白质活性的变化,以及连接蛋白43 (Connexin43,CX43)mRNA和蛋白表达水平的变化,探讨宫缩乏力性产后出血产妇子宫平滑肌自发性收缩功能和收缩潜能的改变,并探讨子宫平滑肌组织中MAPK信号转导通路活化水平和CX43表达变化、及其相关性与宫缩乏力性产后出血发病的关系。
方法
采用等长张力测定方法检测30例宫缩乏力性产后出血产妇(病例组:排除因软产道损伤、胎盘因素、凝血功能障碍引起的产后出血产妇)和30例正常产妇(对照组:同期无产后出血产妇)子宫下段平滑肌收缩功能,并检测使用催产素诱导后其收缩潜能的变化情况。采用蛋白免疫印迹(Western blotting)技术检测病例组和对照组子宫下段平滑肌组织中CX43蛋白和MAPK信号转导通路中ERK1/2、JNK1/2和p38磷酸化蛋白水平。
采用实时荧光定量聚合酶链反应(real-time PCR)技术检测病例组和对照组子宫下段平滑肌组织中CX43mRNA表达。
结果
1.病例组子宫平滑肌自发性收缩的活动力低于对照组,差异有统计学意义(P<0.05),主要表现在收缩频率上,病例组子宫平滑肌收缩频率低于对照组,差异有统计学意义(P<0.05)。
2.以子宫平滑肌自发性收缩活动力为72.66g·次/h作为诊断点,评估宫缩乏力性产后出血的ROC曲线下面积(AUC)为0.802,灵敏度为0.867,特异度为0.700。
3.催产素诱导的离体子宫平滑肌收缩频率和收缩幅度均显著增加,差异有统计学意义(P<0.01),且病例组的收缩潜能低于对照组,差异有统计学意义(P<0.05)。
4.病例组产妇子宫平滑肌组织中p-ERK1/2表达水平低于对照组,差异有统计学意义(P<0.01),病例组产妇子宫平滑肌组织中p-JNK1/2、p-P38表达水平均低于对照组,差异有统计学意义(P<0.05)。
5.两组产妇子宫平滑肌组织中p-ERK1/2、p-JNK1/2和p-P38表达量两两之间呈正相关(P<0.05)。
6.两组产妇子宫平滑肌组织中p-ERK1/2、p-JNK1/2、p-P38表达量与其自发性收缩活动力均呈正相关(P<0.05)。
7.病例组产妇子宫平滑肌组织中CX43mRNA相对表达量及CX43蛋白表达量均低于对照组,差异有统计学意义(P<0.05)。
8.两组产妇子宫平滑肌组织中CX43mRNA及其蛋白表达量与p-ERK1/2、p-JNK1/2、p-P38表达水平呈正相关(P<0.05)。
9.两组产妇子宫平滑肌组织中CX43mRNA及蛋白水平分别与收缩活动力呈正相关(P<0.05)。
结论
1.宫缩乏力性产后出血产妇子宫平滑肌的收缩功能比正常产妇差,可能主要源于其收缩频率低于正常者。
2.催产素诱导的子宫平滑肌收缩显著增加其收缩频率及收缩幅度;催产素诱导的病例组子宫平滑肌收缩潜能低于对照组,提示宫缩乏力性产后出血产妇子宫平滑肌对催产素的反应性低于宫缩正常者。
3.子宫平滑肌组织中ERK1/2、JNK1/2及p38的活化水平与其收缩活动力呈正相关,表明MAPK信号通路的活化调控子宫平滑肌的收缩功能。
4.宫缩乏力性产后出血产妇子宫平滑肌中ERK1/2、JNK1/2及p38亚家族成员的活化水平低于对照组,提示MAPK信号通路激活受阻与宫缩乏力性产后出血的发生相关,且三者间存在相关性,提示三条通路共同参与宫缩乏力性产后出血的发生发展。
5.子宫平滑肌组织中CX43表达下降参与宫缩乏力性产后出血的发生。
6.CX43mRNA和蛋白的表达水平与p-ERK1/2、p-JNK、p-P38表达量呈正相关,提示MAPK信号转导通路与CX43在宫缩乏力性产后出血的发生发展中有促进或协同作用。
Objective
To investigate the contractility and contract potentiality of myometrium from postpartum hemorrhage parturient caused by uterine atony,study the expression and alteration of extracellular-signal regulated kinase1(ERKl/2)and c-jun N-terminal kinase(JNKl/2) and p38 in myometrium from them, research the variation of Connexin43(CX43) mRNA and the protein levels, discuss the change of contractility and potentiality of myometrium from postpartum hemorrhage parturient caused by uterine atony ,and to determin the significance of mitogen-activated protein kinase(MAPK) pathway and CX43 in the pathogenesis of postpartum hemorrhage(PPH),analyze the relationship between MAPK activation and CX43 levels.
Methods
Isometric tension recording was used for 30 uterus smooth muscle samples in PPH patients of atony (cases: ruled out the PPH patients possibility occurs of retained placental fragments, genital tract trauma and coagulopathy)and 30 normal parturitions (controls:the period parturient without PPH)to detect the contractility and its potentiality induced by oxytocin.
The levels of CX43,phosphorylation of ERK1,JNK1and p38MAPK in myometrium of cases and controls were determined by western blotting.
ALL of tissues of cases and their controls were detected for the mRNA of CX43 by Real-time fluorescent quantitative reverse transcription PCR.
Result
1.The contractility of myometriums in the case group were significanctly lower than that of their controls(P<0.05),the differences were mainly caused by the frequency of constriction(P<0.05).
2.To evaluate the postpartum hemorrhage of uterine atony by the diagnosis which constriction acitivity was 72.66 g·times an hour,the area under curve of ROC is 0.802,the insensitivity is 0.867 and the specificity was 0.700.
3.The frequency and range of the constriction induced by oxytocin were significantly increased(P<0.01).The contract potentiality of uterine atony group was lower than that of their controls(P<0.05).
4.In the uterine atony group,the expression of p-ERK1/2、p-JNK1/2 and p-P38 in myometrium were lower than that of their controls ( P <0.05),especially of the p-ERK1/2(P<0.01).
5.There were positive correlation among the expression of p-ERK1/2、p-JNK1/2 and p-P38 (P<0.05).
6. There were positive correlation between the expression of p-ERK1/2、p-JNK1/2、p-P38 and their contraction activities(P<0.05).
7. In the uterine atony group,the expression of CX43mRNA and their protein levels in myometrium were lower than that of their controls(P<0.05).
8.The CX43mRNA levels and its protein quantum were siginificantly correlated with the expression of p-ERK1/2、p-JNK1/2 and p-P38 in uterus smooth muscle(P<0.05).
9. The CX43mRNA levels in myometrium were positively correlated with contraction activity(P<0.05).Also is the protein levels of CX43.
Conclusion
1.The contractility of atony PPH women were lower than that of the controls,it may mainly composed of the difference of frequency of constriction.
2.The constriction induced by oxytocin were significantly increased in both of the frequency and range.The contract potentiality induced by oxytocin of utrine atony samples were lower than that of the controls,may suggest that its reactivity to oxytocin were poor than that of the non-atony women.
3.There were correlations among the activities of ERK1/2、JNK1/2、p38 and constriction,implied that the MAPK signal pathway can regulate the constriction of uterus smooth muscle.
4.In the uterine atony group,the expression of p-ERK1/2、p-JNK1/2 and p-P38 in myometrium were lower than that of their controls,and there were correlations among the three pathways,hinted that the interruption of MAPK signal pathway activate, may correlated with and corporately join the development of PPH.
5.The lower exprssion of CX43 in myometrium may play an important role in pathogenesis of PPH.
6.The expression of CX43mRNA and its proteins were positively correlated with the level of p-ERK1/2、p-JNK1/2 and p-P38,suggested that the MAPK signal pathway may promote the role of CX43 in pathogenesis of PPH.
引文
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