胎盘血管病变发病机理的研究
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摘要
胎盘血管病变可导致妊娠结局不良,其中包括大多数的产前胎儿并发症,如胎儿宫内发育受限(IUGR),以及远期的胎儿并发症如小脑麻痹,而且还与母体的妊娠高血压综合征(PIE)有关。临床研究显示此病变可以被脐动脉多普勒超声检查所识别和诊断,但此病变及其胎儿并发症的病因及发病机理至今未明。
初步的研究显示在胎盘血管病变的胎儿中存在有血小板的激活并认为与内皮细胞损伤有关,因此对内皮细胞的功能性研究在胎盘血管病变的发生中成为关注的焦点。研究表明胎盘绒毛的微血管内皮细胞激活和受损在胎盘血管病变的发病机制中起到关键性的作用,而且这种组织对损伤的反应可能是一种炎性反应。最近的研究表明胎儿的炎性反应、感染和先天性免疫反应与胎盘血管病变相关。最新资料显示IUGR患儿在成年后动脉粥样硬化、心血管疾病和代谢性疾病的发病率显著升高。
动脉粥样硬化是血管内皮对损伤的反应,同时伴有单个核细胞、细胞因子、生长因子、脂蛋白的聚集以及细胞间基质的异常表达,并与感染、炎症和先天性免疫反应相关。而且在胎盘血管病变的胎儿循环中也存在着可导致成人动脉粥样硬化相同的危险因子及基因易感性。
本研究通过应用分子生物学及免疫学技术将进一步阐明微血管内皮激活与受损、炎性反应以及免疫反应在围产期发病中的重要意义,探讨胎盘血管病变与成人动脉粥样硬化疾病的相关性,希望发现与此病发生有关的基因与信号传导路径,试图寻求免疫及基因调控措施、达到对妊娠结局不良的预防与治疗。
第一部分:胎盘血管病变与正常妊娠人类基因组差异表达的研究
目的:胎盘血管病变可能导致人类妊娠并发症以及结局不良。临床研究显示此病变可以被脐动脉多普勒超声检查所识别和诊断。近来的研究表明在胎盘血管病中存在胎盘绒毛的微血管内皮细胞激活和促炎的细胞因子应答。并且胎盘内皮细胞激活和受损已被证明是胎盘血管病变的一个特征。虽然为了阐明该病的发病机制已经做了大量的研究,但此病变及其胎儿并发症的病因及发病机理至今未明。本研究应用22 K人类基因组寡核苷酸芯片,筛选了胎盘血管病患者和正常妊娠者胎盘组织中的差异表达基因,并应用实时定量聚合酶链反应(PCR)验证了部分差异基因的表达,进行了分子生物信息学分析,探讨差异基因群与胎盘血管病之间可能存在的联系,并将以此为切入点研究胎盘血管病的发生机制。
材料与方法:
1.标本收集
2.人类基因组寡核苷酸芯片(22K)
*木胎盘组织总RNA的提取
*对样品RNA进行荧光标记
*芯片杂交前预处理
*杂交与清洗
*芯片扫描
*芯片图像的采集与数据分析
3.提取RNA,进行实时定量PCR
4.统计学分析
结果:
一、芯片结果信息比较分析
经过两张芯片间差异基因表达的比较,我们发现在胎盘血管病中存在10个基因表达水平显著改变≥2或≤0.5,它们包括SNFT,SLC18A2,MT1H,MTIX,HSPA6,HSPA1A,MT1E,MT1L,SSI-1和H1F0,这些基因中大多数为信号传导因子,其中有9个在胎盘血管病中上调,只有1个下调。
二、实时定量PCR结果分析
4个差异基因在胎盘血管病与正常胎盘中的表达通过定量PCR检测。经过数据统计分析,它们在患有胎盘血管病的胎盘组织中的表达均较正常胎盘组织中的表达升高,与芯片结果一致。
结论:胎盘血管病是一种炎性疾病,具有血管壁内皮细胞激活的特征。HSPA1A,HAPA6,MT1L,MT1E,MT1H和MTIX在细胞抵抗氧化应激中可能作为第二类抗氧化剂起到保护作用。SLC18A2在胎盘血管床中也可能作为一种保护机制预防血管收缩从而保证为胎儿提供稳定的血流。SSI-1和SNFT可能抑制细胞因子的信号传导,而H1F0可能参与了转录活性和细胞分化的调控。总之,这些基因有可能通过转录因子的活化参与了内皮细胞激活。
第二部分:胎盘血管病变发病的相关因子在胎盘组织及微血管内皮细胞中表达的研究
目的:胎盘循环中的血管病变可以导致人类妊娠的并发症(如:PIE)和妊娠结局不良(如:IUGR,胎儿宫内窘迫等)。在胎盘组织的母体-胎儿面致炎和抗炎的细胞因子至少部分参与病变的发生。最近的研究表明在胎盘血管病变中胎儿的感染和炎性反应与先天性免疫反应相关。并且已经有直接的证据证明在胎盘血管病变中存在胎盘绒毛的微血管内皮细胞激活和炎性因子的应答。研究表明胎盘中内皮细胞受损和激活是胎盘血管病变的一个特征。在本研究中,我们选择与血管病变及炎性疾病发病关系密切的因子如:热休克蛋白(HSP)和白介素(IL)进行了检测,以探讨它们在该病发生发展中的作用及机制。
材料与方法:
1.标本收集
2.免疫组织化学
3.应用标记CD31的免疫磁珠分离纯化胎盘微血管内皮细胞
4.提取RNA,进行实时定量PCR
5.蛋白提取与蛋白印记分析(Western-blot)
6.统计学分析
结果:
1.免疫组化结果分析
结果发现在胎盘微血管中HSP27和HSP70主要表达在内皮细胞和平滑肌细胞,在研究组和对照组均较强;IL-10的表达非常弱,而且阳性结果较少,无法进行对比分析;而IL-18的表达却主要限于内皮细胞,且较弱,经过比较可以得出实验组较对照组表达阳性明显增强。
2.胎盘微血管内皮细胞的鉴定
从胎盘绒毛的微血管分离后,结合有标记CD31免疫磁珠的内皮细胞,用vWF抗体验证其纯度达到90%以上。
3.实时定量PCR结果分析
我们通过定量PCR检测了HSP27、HSP70、IL-10和IL-18在胎盘组织及微血管内皮细胞中的表达。IL-10经过反复多次试验,无论在胎盘组织还是血管内皮细胞(包括观察组及对照组)均未扩增出目的条带,因此无法进行对比定量分析;无论是胎盘组织中还是微血管内皮细胞中,实验组较正常组HSP27、HSP70和IL-18的表达均上调(P＜0.05)。
4.Western-blot结果分析
为了比较HSP27和HSP70蛋白的表达,我们进行了Western-blot。结果显示在胎盘组织及微血管内皮细胞中,实验组较正常组HSP27和HSP70的表达均上调(P＜0.05)。
5.临床结果分析
实验组的孕妇分娩较早,婴儿出生体重也减轻,在这组中出生体重相对胎龄的百分数也是减低的。经过相关分析,IL-18的表达与孕妇身高呈负相关,与宫高和胎儿身高呈正相关(P＜0.05);HSP27的表达与胎次、胎儿体重和出生体重相对胎龄的百分数呈负相关(P＜0.05);HSP70的表达与胎儿出生时的体重呈负相关(P＜0.05);IL-18和HSP27的表达呈正相关(P＜0.05);HSP27和HSP70的表达也呈正相关(P＜0.05)。
结论:IL-18、HSP27和HSP70与胎盘血管病的发病机制相关,并认为热休克蛋白作为转录因子通过多渠道对IL-18的信号传导起调节作用。IL-18、HSP27和HSP70在胎盘微血管内皮细胞中表达的升高进一步导致胎盘组织中的升高。本研究为胎盘血管病中炎症应答和内皮损伤的重要性提供了进一步的证据。我们推测IL-18以及其他相关细胞因子可作为介质导致内皮受损和炎性应答,并参与了胎盘血管病的发生和发展。
第三部分:CD4+CD25+调节性T细胞在胎盘血管病变中的研究
目的:近代生殖免疫学研究认为,妊娠是一种成功的半同种移植,妊娠的成功有赖于妊娠妇女对胚胎半同种抗原所表现的一种免疫耐受。最近的研究表明,CD4+CD25+调节性T细胞(T regulatory cell,Treg)可能是诱导母胎免疫耐受的主要因素。Treg是不同于Th1和Th2的具有免疫调节功能的T细胞群体,是机体以主动方式获得和维持自身耐受的一种重要方式。转录因子Foxp3(叉状头/翅膀状螺旋回转录因子)是维持CD4+CD25+Treg发育和功能的重要调节基因,在正常人中可作为CD4+CD25+Treg的特异性鉴定标志。本研究拟通过流式细胞术检测胎盘血管病与正常孕妇外周血中CD4+CD25+Foxp3+Treg的表达率,以探讨Treg在胎盘血管病发病中的作用。
材料与方法:
1.留取标本:实验组与对照组孕妇分别取外周血2ml,均用EDTA抗凝;
2.分离单个核细胞:用Ficoll淋巴细胞分离液分离单个核细胞;
3.流式细胞术:检测新鲜单个核细胞中CD4+CD25+Foxp3+Treg的表达率;
4.统计学分析
结果:试验组与对照组相比较,CD4+细胞率P值＜0.05,存在显著性差异;CD25+/CD4+、Foxp3+/CD4+和CD25+Foxp3+/CD4+细胞率,P值均＞0.05,提示无显著性差异。
结论:本研究尚未发现CD4+CD25+Foxp3+Treg在胎盘血管病组与正常妊娠组之间存在显著差异表达,可能与观察例数受限有关,因此对于免疫耐受是否参与胎盘血管病的发病机理仍需要开展进一步的大样本研究。
Placental vascular disease may result in adverse outcomes of human pregnancy, including most prenatal fetal complications such as fetal Intrauterine growth restriction(IUGR),and long-term complications such as cerebellum palsy,and is associated with materal gestational hypertension syndrome.Clinical researches have shown that this disease may be identified and diagnosed antenatally by the study of umbilical artery Doppler flow velocity waveforms.However,up to date the cause and pathogenisis of this disease and fetal complications are unknown.
Preliminary research has shown that in fetal circulation with placental vascular disease thrombocytic activation is present and is associated with endothelial injury. Therefore,the functional investigations of endothelial cells became the focus in the pathogenesis of placental vascular disease.Researches have indicated that microvascular endothelial activation and injury of placental villi may play a key role in the pathogenesis of placental vascular disease.And the response of tissues to injury may be an inflammatory response.Recent researches have shown that fetal inflammatory response,infection and innate immunity are involved with placental vascular disease.
Atherosclerosis has been defined as the response of vascular endothelium to injury accompanied with the aggregation of mononuclear cells,cytokines,growth factors and lipoprotein,as well as abnormal expressions of intercellular matrix.And it is associated with infection,inflammatory and innate immunity.Furthermore,similar risk factors and gene susceptibility which may result in adult atherosclerosis exist in fetal circulation with placental vascular disease.
In this study we will further elucidate the important significance of microvascular endothelial activation and injury,inflammatory response and immune response in the morbidity during perinatal period by using molecular biology and immunology techniques.We will also approach the correlation between placental vascular disease and adult atherosclerosis and investigate related genes and signal transduction pathways with the occurrence of this disease,in order to explore the effective measures about immunology and gene regulation to prevent and treat the adverse outcomes of human pregnancy.
PartⅠScreening and Identification of Differentially Regulated Genes in Placental Vascular Disease
Objective:Vascular disease in placental circulation can result in complications of human pregnancy and adverse outcomes.Clinical research has shown that this disease could be identified antenatally by umbilical artery Doppler flow velocity waveforms. Recent researches have indicated that there has been microvascular endothelial cell activation of placental villus and a pro-inflammatory cytokine response in the placental vascular disease.It has been suggested that injury and activation of endothelial cells in the fetal placenta is a feature of placental vascular disease.Though a lot of researches have been done to clarify the mechanism of this disease,up to date the pathogenesis of this disease is still unknown.In this study we perform a gene expression profiling study of placental tissue from women with and without vascular disease by using 22k Human Genome Oligo Array to approach the relation between the different genes and placental vascular disease,which will point out the direction to understand the pathogenesis of the placental vascular disease.
Material and Methods:
1.Specimen collection
2.Human Genome Oligo Array(22 K)
* Extraction and purification of RNA from placental tissues
* cDNA Synthesis and fluorescence labeling
* Microarray Pretreatment before Hybridization
* Microarray Hybridization and Microarray Washing After Hybridization
* Microarray scanning
* Raw Data Generation and Microarray data analysis
3.Extraction of RNA and real-time quantitative polymerase chain reaction(PCR)
4.Statistical analysis
Results:
The analysis of microarray results
By comparative differential gene expression analysis between two microarrays, we found 10 genes to be significantly altered in their expression levels≥2 or≤0.5, which comprising of SNFT,SLC18A2,MT1H,MTIX,HSPA6,HSPA1A,MT1E, MT1L,SSI-1,H1F0.Among them 9 genes were up-regulated and 1 gene was down-regulated in placental vascular diseases.
Real-time Quantitative PCR analysis
Expressions of four differential genes in placental tissues with placental vascular disease and normal pregnancy were detected through quantitative PCR.Their expressions were up-regulated in placental tissue with placental vascular disease in comparison to normal pregnancy.
Conclusion:Placental vascular disease is an inflammatory disease characterized by the activation of endothelial cells in the vessel wall.HSPA1A,HAPA6,MT1L, MT1E,MT1H and MTIX all act as a secondary antioxidant in cellular protection system against oxidative stress.SLC18A2 may serve as a protective mechanism in the placental vascular beds.SSI-1 and SNFT may inhibit signaling of cytokines.And H1F0 may contribute to participation in the modulation of transcriptional activity and cell differentiation.These genes can participate in endothelial activation through the activation of the transcription factors.
PartⅡThe Expressions of the Related Factors in Placental Tissues and Microvascular Endothelial Cells with Placental Vascular Disease
Objective:Vascular disease in placental circulation can result in complications of human pregnancy such as preeclampsia(PIE)and adverse outcomes such as fetal intrauterine growth restriction(IUGR),as well as fetal distress in uterus.Imbalance of tissue pro-inflammatory and anti-inflammatory cytokines at the maternal-fetal interface may be partly involved in disease causation.Recent researches have indicated that the pro-inflammatory response and infection in the fatal are associated with innate immuno-response in the placental vascular disease.And there have been direct evidence for microvascular endothelial cell activation of placental villus and a pro-inflammatory cytokine response in the placental vascular disease.It has been suggested that injury and activation of endothelial cells in the fetal placenta is a feature of placental vascular disease.In this study,we detect some related factors with vascular disease and inflammatory disease such as heat shock proteins and interleukins to approach their functions and machanism in placental vascular disease.
Material and Methods:
1.Specimen collection
2.Immunohistochemistry
3.Isolation and purification of placental microvascular endothelial cells with Dynabeads CD31
4.Extraction of RNA and real-time quantitative PCR
5.Extraction of protein and Western-blot analysis
6.Statistical analysis
Results:
Immunohistochemical analysis
Results have shown that HSP27 and HSP70 are expressed in endothelial cells and smooth muscle cells in the placental microvessels.The immunostaining is very strong in the placental tissues of both study group and control group.The expression of IL-10 is too poor to analysize.IL-18 is mostly expressed in endothelial cells in placental microvessels and there was significant difference in the expression of IL-18 in placental microvascular endothelial cells between PVD and normal pregnancy(P＜0.05).
Identification of microvascular endothelial cells
The purity of microvascular endothelial cells,which were bound to Dynabeads CD31 after isolation from microvasculation of placental villi,was above 90%with vWF antibody by using flow cytometry.
Real-time Quantitative PCR analysis
The mRNA expressions of IL-10,IL-18,HSP27 and HSP70 in placental tissue and microvascular endothelial cell were detected through quantitative PCR.Trying so many times we can not amply the IL-10 mRNA and can not compare the expressions between the study group and control group yet.The mRNA expressions of IL-18, HSP27 and HSP70 were up-regulated in placental tissue and microvascular endothelial cells from PVD in comparison to normal pregnancies(P＜0.05).
Western-blot analysis
We detected the expressions of HSP27 and HSP70 protein in placental tissues and microvascular endothelial cells by using western-blot.The results presented that the expressions of HSP27 and HSP70 were significantly up-regulated both in placental tissues and in microvascular endothelial cells from PVD in comparison to normal pregnancy(P＜0.05).
Clinical characteristics
The pregnancies with PVD had earlier delivery and lower birth weight.The birth weights of the babies in the study group fell into the lower percentile for gestational age.Maternal body height had negative correlation,fetal body height and metra-height had positive correlations with the expression of IL-18 mRNA(P＜0.05). Yet the expression of HSP27 has negative correlations with gestational times,infant birth weight and the percentile birth weight for gestational age(P＜0.05).The expressions of HSP70 had negative correlation with infant birth weight respectively (P＜0.05).The expressions of IL-18 and HSP27 have positive correlation(P＜0.05). The expressions of HSP70 and HSP27 have positive correlation(P＜0.05).
Conclusion:IL-18,HSP27 and HSP70 might be associated with the pathogenesis of PVD.HSPs may play a key role in IL-18 signaling via several signal transduction pathways.The enhanced expression of IL-18,HSP27 and HSP70 in placental microvascular endothelial cells possibly makes contribution to their elevation in placental tissues.Our finding adds evidence supporting the importance of inflammatory response and endothelial injury in this disease.We proposed that IL-18 and other pro-inflammatory cytokines might be among the mediators leading to endothelial dysfunction and inflammatory response,thus it may be associated with the pathogenesis of PVD.
PartⅢThe Expression of CD4+CD25+ Regulatory T Cells in Placental Vascular Disease
Objective:Modern reproductive immunology has reported that pregnancy is a successful semi-homotransplantation.The pregnant success depends on a sort of immune tolerance,which is the response of pregnant women to the semi-aUoantigen of embryo.Recent studies have indicated that CD4+CD25+ regulatory T cells(T regulatory cell,Treg)may be the main factor to induce immune tolerance.Treg is the cell colony possessing the function of immune regulation and an important means to gain and keep self-tolerance in active mode.Transcription factor Foxp3 is important regular gene to keep the development and functions of CD4+CD25+Treg,and it is referred as the special sign of CD4+CD25+Treg.In this study we examine the expression of CD4+CD25+Foxp3+Treg in maternal blood with placental vascular disease and normal pregnancy to approach the role of Treg in the pathogenesis of placental vascular disease.
Material and Methods:
1.Specimen collection:2ml peripheral blood was collected,anti-coagulated with EDTA.
2.Isolation of mononuclear cells:Mononulcear cells were isolated with Ficoll.
3.Flow cytometry:The expressions of CD4+CD25+Foxp3+Treg cells were examined by using flow cytometry.
4.Statistical analysis
Results:The expression of CD4+ cells is up-regulated when study group comparing with control group(P＜0.05).The expressions of CD25+CD4+,Foxp3+CD4+ and CD4+CD25+Foxp3+ Treg cells have no difference between placental vascular disease and normal pregnancies(P＞0.05).
Conclusion:According to the results,we did not find the different expressions of CD4+CD25+Foxp3+ Treg between the study group and the control group.It may be associated with limited cases.Therefore,further researches need be carried out to elucidate whether immune tolerance participates in the pathogenesis of placental vascular disease.
初步的研究显示在胎盘血管病变的胎儿中存在有血小板的激活并认为与内皮细胞损伤有关,因此对内皮细胞的功能性研究在胎盘血管病变的发生中成为关注的焦点。研究表明胎盘绒毛的微血管内皮细胞激活和受损在胎盘血管病变的发病机制中起到关键性的作用,而且这种组织对损伤的反应可能是一种炎性反应。最近的研究表明胎儿的炎性反应、感染和先天性免疫反应与胎盘血管病变相关。最新资料显示IUGR患儿在成年后动脉粥样硬化、心血管疾病和代谢性疾病的发病率显著升高。
动脉粥样硬化是血管内皮对损伤的反应,同时伴有单个核细胞、细胞因子、生长因子、脂蛋白的聚集以及细胞间基质的异常表达,并与感染、炎症和先天性免疫反应相关。而且在胎盘血管病变的胎儿循环中也存在着可导致成人动脉粥样硬化相同的危险因子及基因易感性。
本研究通过应用分子生物学及免疫学技术将进一步阐明微血管内皮激活与受损、炎性反应以及免疫反应在围产期发病中的重要意义,探讨胎盘血管病变与成人动脉粥样硬化疾病的相关性,希望发现与此病发生有关的基因与信号传导路径,试图寻求免疫及基因调控措施、达到对妊娠结局不良的预防与治疗。
第一部分:胎盘血管病变与正常妊娠人类基因组差异表达的研究
目的:胎盘血管病变可能导致人类妊娠并发症以及结局不良。临床研究显示此病变可以被脐动脉多普勒超声检查所识别和诊断。近来的研究表明在胎盘血管病中存在胎盘绒毛的微血管内皮细胞激活和促炎的细胞因子应答。并且胎盘内皮细胞激活和受损已被证明是胎盘血管病变的一个特征。虽然为了阐明该病的发病机制已经做了大量的研究,但此病变及其胎儿并发症的病因及发病机理至今未明。本研究应用22 K人类基因组寡核苷酸芯片,筛选了胎盘血管病患者和正常妊娠者胎盘组织中的差异表达基因,并应用实时定量聚合酶链反应(PCR)验证了部分差异基因的表达,进行了分子生物信息学分析,探讨差异基因群与胎盘血管病之间可能存在的联系,并将以此为切入点研究胎盘血管病的发生机制。
材料与方法:
1.标本收集
2.人类基因组寡核苷酸芯片(22K)
*木胎盘组织总RNA的提取
*对样品RNA进行荧光标记
*芯片杂交前预处理
*杂交与清洗
*芯片扫描
*芯片图像的采集与数据分析
3.提取RNA,进行实时定量PCR
4.统计学分析
结果:
一、芯片结果信息比较分析
经过两张芯片间差异基因表达的比较,我们发现在胎盘血管病中存在10个基因表达水平显著改变≥2或≤0.5,它们包括SNFT,SLC18A2,MT1H,MTIX,HSPA6,HSPA1A,MT1E,MT1L,SSI-1和H1F0,这些基因中大多数为信号传导因子,其中有9个在胎盘血管病中上调,只有1个下调。
二、实时定量PCR结果分析
4个差异基因在胎盘血管病与正常胎盘中的表达通过定量PCR检测。经过数据统计分析,它们在患有胎盘血管病的胎盘组织中的表达均较正常胎盘组织中的表达升高,与芯片结果一致。
结论:胎盘血管病是一种炎性疾病,具有血管壁内皮细胞激活的特征。HSPA1A,HAPA6,MT1L,MT1E,MT1H和MTIX在细胞抵抗氧化应激中可能作为第二类抗氧化剂起到保护作用。SLC18A2在胎盘血管床中也可能作为一种保护机制预防血管收缩从而保证为胎儿提供稳定的血流。SSI-1和SNFT可能抑制细胞因子的信号传导,而H1F0可能参与了转录活性和细胞分化的调控。总之,这些基因有可能通过转录因子的活化参与了内皮细胞激活。
第二部分:胎盘血管病变发病的相关因子在胎盘组织及微血管内皮细胞中表达的研究
目的:胎盘循环中的血管病变可以导致人类妊娠的并发症(如:PIE)和妊娠结局不良(如:IUGR,胎儿宫内窘迫等)。在胎盘组织的母体-胎儿面致炎和抗炎的细胞因子至少部分参与病变的发生。最近的研究表明在胎盘血管病变中胎儿的感染和炎性反应与先天性免疫反应相关。并且已经有直接的证据证明在胎盘血管病变中存在胎盘绒毛的微血管内皮细胞激活和炎性因子的应答。研究表明胎盘中内皮细胞受损和激活是胎盘血管病变的一个特征。在本研究中,我们选择与血管病变及炎性疾病发病关系密切的因子如:热休克蛋白(HSP)和白介素(IL)进行了检测,以探讨它们在该病发生发展中的作用及机制。
材料与方法:
1.标本收集
2.免疫组织化学
3.应用标记CD31的免疫磁珠分离纯化胎盘微血管内皮细胞
4.提取RNA,进行实时定量PCR
5.蛋白提取与蛋白印记分析(Western-blot)
6.统计学分析
结果:
1.免疫组化结果分析
结果发现在胎盘微血管中HSP27和HSP70主要表达在内皮细胞和平滑肌细胞,在研究组和对照组均较强;IL-10的表达非常弱,而且阳性结果较少,无法进行对比分析;而IL-18的表达却主要限于内皮细胞,且较弱,经过比较可以得出实验组较对照组表达阳性明显增强。
2.胎盘微血管内皮细胞的鉴定
从胎盘绒毛的微血管分离后,结合有标记CD31免疫磁珠的内皮细胞,用vWF抗体验证其纯度达到90%以上。
3.实时定量PCR结果分析
我们通过定量PCR检测了HSP27、HSP70、IL-10和IL-18在胎盘组织及微血管内皮细胞中的表达。IL-10经过反复多次试验,无论在胎盘组织还是血管内皮细胞(包括观察组及对照组)均未扩增出目的条带,因此无法进行对比定量分析;无论是胎盘组织中还是微血管内皮细胞中,实验组较正常组HSP27、HSP70和IL-18的表达均上调(P＜0.05)。
4.Western-blot结果分析
为了比较HSP27和HSP70蛋白的表达,我们进行了Western-blot。结果显示在胎盘组织及微血管内皮细胞中,实验组较正常组HSP27和HSP70的表达均上调(P＜0.05)。
5.临床结果分析
实验组的孕妇分娩较早,婴儿出生体重也减轻,在这组中出生体重相对胎龄的百分数也是减低的。经过相关分析,IL-18的表达与孕妇身高呈负相关,与宫高和胎儿身高呈正相关(P＜0.05);HSP27的表达与胎次、胎儿体重和出生体重相对胎龄的百分数呈负相关(P＜0.05);HSP70的表达与胎儿出生时的体重呈负相关(P＜0.05);IL-18和HSP27的表达呈正相关(P＜0.05);HSP27和HSP70的表达也呈正相关(P＜0.05)。
结论:IL-18、HSP27和HSP70与胎盘血管病的发病机制相关,并认为热休克蛋白作为转录因子通过多渠道对IL-18的信号传导起调节作用。IL-18、HSP27和HSP70在胎盘微血管内皮细胞中表达的升高进一步导致胎盘组织中的升高。本研究为胎盘血管病中炎症应答和内皮损伤的重要性提供了进一步的证据。我们推测IL-18以及其他相关细胞因子可作为介质导致内皮受损和炎性应答,并参与了胎盘血管病的发生和发展。
第三部分:CD4+CD25+调节性T细胞在胎盘血管病变中的研究
目的:近代生殖免疫学研究认为,妊娠是一种成功的半同种移植,妊娠的成功有赖于妊娠妇女对胚胎半同种抗原所表现的一种免疫耐受。最近的研究表明,CD4+CD25+调节性T细胞(T regulatory cell,Treg)可能是诱导母胎免疫耐受的主要因素。Treg是不同于Th1和Th2的具有免疫调节功能的T细胞群体,是机体以主动方式获得和维持自身耐受的一种重要方式。转录因子Foxp3(叉状头/翅膀状螺旋回转录因子)是维持CD4+CD25+Treg发育和功能的重要调节基因,在正常人中可作为CD4+CD25+Treg的特异性鉴定标志。本研究拟通过流式细胞术检测胎盘血管病与正常孕妇外周血中CD4+CD25+Foxp3+Treg的表达率,以探讨Treg在胎盘血管病发病中的作用。
材料与方法:
1.留取标本:实验组与对照组孕妇分别取外周血2ml,均用EDTA抗凝;
2.分离单个核细胞:用Ficoll淋巴细胞分离液分离单个核细胞;
3.流式细胞术:检测新鲜单个核细胞中CD4+CD25+Foxp3+Treg的表达率;
4.统计学分析
结果:试验组与对照组相比较,CD4+细胞率P值＜0.05,存在显著性差异;CD25+/CD4+、Foxp3+/CD4+和CD25+Foxp3+/CD4+细胞率,P值均＞0.05,提示无显著性差异。
结论:本研究尚未发现CD4+CD25+Foxp3+Treg在胎盘血管病组与正常妊娠组之间存在显著差异表达,可能与观察例数受限有关,因此对于免疫耐受是否参与胎盘血管病的发病机理仍需要开展进一步的大样本研究。
Placental vascular disease may result in adverse outcomes of human pregnancy, including most prenatal fetal complications such as fetal Intrauterine growth restriction(IUGR),and long-term complications such as cerebellum palsy,and is associated with materal gestational hypertension syndrome.Clinical researches have shown that this disease may be identified and diagnosed antenatally by the study of umbilical artery Doppler flow velocity waveforms.However,up to date the cause and pathogenisis of this disease and fetal complications are unknown.
Preliminary research has shown that in fetal circulation with placental vascular disease thrombocytic activation is present and is associated with endothelial injury. Therefore,the functional investigations of endothelial cells became the focus in the pathogenesis of placental vascular disease.Researches have indicated that microvascular endothelial activation and injury of placental villi may play a key role in the pathogenesis of placental vascular disease.And the response of tissues to injury may be an inflammatory response.Recent researches have shown that fetal inflammatory response,infection and innate immunity are involved with placental vascular disease.
Atherosclerosis has been defined as the response of vascular endothelium to injury accompanied with the aggregation of mononuclear cells,cytokines,growth factors and lipoprotein,as well as abnormal expressions of intercellular matrix.And it is associated with infection,inflammatory and innate immunity.Furthermore,similar risk factors and gene susceptibility which may result in adult atherosclerosis exist in fetal circulation with placental vascular disease.
In this study we will further elucidate the important significance of microvascular endothelial activation and injury,inflammatory response and immune response in the morbidity during perinatal period by using molecular biology and immunology techniques.We will also approach the correlation between placental vascular disease and adult atherosclerosis and investigate related genes and signal transduction pathways with the occurrence of this disease,in order to explore the effective measures about immunology and gene regulation to prevent and treat the adverse outcomes of human pregnancy.
PartⅠScreening and Identification of Differentially Regulated Genes in Placental Vascular Disease
Objective:Vascular disease in placental circulation can result in complications of human pregnancy and adverse outcomes.Clinical research has shown that this disease could be identified antenatally by umbilical artery Doppler flow velocity waveforms. Recent researches have indicated that there has been microvascular endothelial cell activation of placental villus and a pro-inflammatory cytokine response in the placental vascular disease.It has been suggested that injury and activation of endothelial cells in the fetal placenta is a feature of placental vascular disease.Though a lot of researches have been done to clarify the mechanism of this disease,up to date the pathogenesis of this disease is still unknown.In this study we perform a gene expression profiling study of placental tissue from women with and without vascular disease by using 22k Human Genome Oligo Array to approach the relation between the different genes and placental vascular disease,which will point out the direction to understand the pathogenesis of the placental vascular disease.
Material and Methods:
1.Specimen collection
2.Human Genome Oligo Array(22 K)
* Extraction and purification of RNA from placental tissues
* cDNA Synthesis and fluorescence labeling
* Microarray Pretreatment before Hybridization
* Microarray Hybridization and Microarray Washing After Hybridization
* Microarray scanning
* Raw Data Generation and Microarray data analysis
3.Extraction of RNA and real-time quantitative polymerase chain reaction(PCR)
4.Statistical analysis
Results:
The analysis of microarray results
By comparative differential gene expression analysis between two microarrays, we found 10 genes to be significantly altered in their expression levels≥2 or≤0.5, which comprising of SNFT,SLC18A2,MT1H,MTIX,HSPA6,HSPA1A,MT1E, MT1L,SSI-1,H1F0.Among them 9 genes were up-regulated and 1 gene was down-regulated in placental vascular diseases.
Real-time Quantitative PCR analysis
Expressions of four differential genes in placental tissues with placental vascular disease and normal pregnancy were detected through quantitative PCR.Their expressions were up-regulated in placental tissue with placental vascular disease in comparison to normal pregnancy.
Conclusion:Placental vascular disease is an inflammatory disease characterized by the activation of endothelial cells in the vessel wall.HSPA1A,HAPA6,MT1L, MT1E,MT1H and MTIX all act as a secondary antioxidant in cellular protection system against oxidative stress.SLC18A2 may serve as a protective mechanism in the placental vascular beds.SSI-1 and SNFT may inhibit signaling of cytokines.And H1F0 may contribute to participation in the modulation of transcriptional activity and cell differentiation.These genes can participate in endothelial activation through the activation of the transcription factors.
PartⅡThe Expressions of the Related Factors in Placental Tissues and Microvascular Endothelial Cells with Placental Vascular Disease
Objective:Vascular disease in placental circulation can result in complications of human pregnancy such as preeclampsia(PIE)and adverse outcomes such as fetal intrauterine growth restriction(IUGR),as well as fetal distress in uterus.Imbalance of tissue pro-inflammatory and anti-inflammatory cytokines at the maternal-fetal interface may be partly involved in disease causation.Recent researches have indicated that the pro-inflammatory response and infection in the fatal are associated with innate immuno-response in the placental vascular disease.And there have been direct evidence for microvascular endothelial cell activation of placental villus and a pro-inflammatory cytokine response in the placental vascular disease.It has been suggested that injury and activation of endothelial cells in the fetal placenta is a feature of placental vascular disease.In this study,we detect some related factors with vascular disease and inflammatory disease such as heat shock proteins and interleukins to approach their functions and machanism in placental vascular disease.
Material and Methods:
1.Specimen collection
2.Immunohistochemistry
3.Isolation and purification of placental microvascular endothelial cells with Dynabeads CD31
4.Extraction of RNA and real-time quantitative PCR
5.Extraction of protein and Western-blot analysis
6.Statistical analysis
Results:
Immunohistochemical analysis
Results have shown that HSP27 and HSP70 are expressed in endothelial cells and smooth muscle cells in the placental microvessels.The immunostaining is very strong in the placental tissues of both study group and control group.The expression of IL-10 is too poor to analysize.IL-18 is mostly expressed in endothelial cells in placental microvessels and there was significant difference in the expression of IL-18 in placental microvascular endothelial cells between PVD and normal pregnancy(P＜0.05).
Identification of microvascular endothelial cells
The purity of microvascular endothelial cells,which were bound to Dynabeads CD31 after isolation from microvasculation of placental villi,was above 90%with vWF antibody by using flow cytometry.
Real-time Quantitative PCR analysis
The mRNA expressions of IL-10,IL-18,HSP27 and HSP70 in placental tissue and microvascular endothelial cell were detected through quantitative PCR.Trying so many times we can not amply the IL-10 mRNA and can not compare the expressions between the study group and control group yet.The mRNA expressions of IL-18, HSP27 and HSP70 were up-regulated in placental tissue and microvascular endothelial cells from PVD in comparison to normal pregnancies(P＜0.05).
Western-blot analysis
We detected the expressions of HSP27 and HSP70 protein in placental tissues and microvascular endothelial cells by using western-blot.The results presented that the expressions of HSP27 and HSP70 were significantly up-regulated both in placental tissues and in microvascular endothelial cells from PVD in comparison to normal pregnancy(P＜0.05).
Clinical characteristics
The pregnancies with PVD had earlier delivery and lower birth weight.The birth weights of the babies in the study group fell into the lower percentile for gestational age.Maternal body height had negative correlation,fetal body height and metra-height had positive correlations with the expression of IL-18 mRNA(P＜0.05). Yet the expression of HSP27 has negative correlations with gestational times,infant birth weight and the percentile birth weight for gestational age(P＜0.05).The expressions of HSP70 had negative correlation with infant birth weight respectively (P＜0.05).The expressions of IL-18 and HSP27 have positive correlation(P＜0.05). The expressions of HSP70 and HSP27 have positive correlation(P＜0.05).
Conclusion:IL-18,HSP27 and HSP70 might be associated with the pathogenesis of PVD.HSPs may play a key role in IL-18 signaling via several signal transduction pathways.The enhanced expression of IL-18,HSP27 and HSP70 in placental microvascular endothelial cells possibly makes contribution to their elevation in placental tissues.Our finding adds evidence supporting the importance of inflammatory response and endothelial injury in this disease.We proposed that IL-18 and other pro-inflammatory cytokines might be among the mediators leading to endothelial dysfunction and inflammatory response,thus it may be associated with the pathogenesis of PVD.
PartⅢThe Expression of CD4+CD25+ Regulatory T Cells in Placental Vascular Disease
Objective:Modern reproductive immunology has reported that pregnancy is a successful semi-homotransplantation.The pregnant success depends on a sort of immune tolerance,which is the response of pregnant women to the semi-aUoantigen of embryo.Recent studies have indicated that CD4+CD25+ regulatory T cells(T regulatory cell,Treg)may be the main factor to induce immune tolerance.Treg is the cell colony possessing the function of immune regulation and an important means to gain and keep self-tolerance in active mode.Transcription factor Foxp3 is important regular gene to keep the development and functions of CD4+CD25+Treg,and it is referred as the special sign of CD4+CD25+Treg.In this study we examine the expression of CD4+CD25+Foxp3+Treg in maternal blood with placental vascular disease and normal pregnancy to approach the role of Treg in the pathogenesis of placental vascular disease.
Material and Methods:
1.Specimen collection:2ml peripheral blood was collected,anti-coagulated with EDTA.
2.Isolation of mononuclear cells:Mononulcear cells were isolated with Ficoll.
3.Flow cytometry:The expressions of CD4+CD25+Foxp3+Treg cells were examined by using flow cytometry.
4.Statistical analysis
Results:The expression of CD4+ cells is up-regulated when study group comparing with control group(P＜0.05).The expressions of CD25+CD4+,Foxp3+CD4+ and CD4+CD25+Foxp3+ Treg cells have no difference between placental vascular disease and normal pregnancies(P＞0.05).
Conclusion:According to the results,we did not find the different expressions of CD4+CD25+Foxp3+ Treg between the study group and the control group.It may be associated with limited cases.Therefore,further researches need be carried out to elucidate whether immune tolerance participates in the pathogenesis of placental vascular disease.
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[5]. ALAIN TEDGUI AND ZIAD MALLAT. (2006) Cytokines in Atherosclerosis: Pathogenic and Regulatory Pathways. Physiol Rev. 86: 515-581.
[6]. Bretelle F, Sabatier F, Shojai R, Agostini A, Dignat-George F, Blanc B, d'Ercole C. (2004) New insight in physiopathology of preeclampsia and intra-uterine growth retardation: role of inflammation. Gynecol Obstet Fertil. 32: 482-489.
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[8]. Lindquist S, Craig EA. (1988) The heat-shock proteins. Annu Rev Genet. 22: 631-677.
[9]. Asea A, Kraeft SK, Kurt-Jones EA, et al. (2000) HSP70 stimulates cytokine production through a CD14-dependant pathway, demonstrating its dual role as a chaperone and cytokine. Nat Med. 6: 435-442.
[10]. Asea A, Kabingu E, Stevenson MA, Calderwood SK. (2000) HSP70 peptide-bearing and peptide-negative preparations act as chaperokines. Cell Stress Chaperones. 5:425-431.
[11]. Shah M, Stanek J, Handwerger S. (1998) Differential localization of heat shock proteins 90, 70, 60 and 27 in human decidua and placenta during pregnancy. Histochem J. 30: 509-518.
[12]. Jirecek S, Hohlagschwandtner M, Tempfer C, Knofler M, Husslein P, Zeisler H. (2002) Serum levels of heat shock protein 70 in patients with preeclampsia: a pilot-study. Wien Klin Wochenschr. 114: 730-732.
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1. Trudinger B, Wang J, Athayde N, Beutler L, Wang X. Association of umbilical placental vascular disease with fetal acute inflammatory cytokine responses. J Soc Gynecol Investig 2002; 9:152-7.
2. Pober JS, Cotran RS. Cytokines and endothelial cell biology. Physiol Rev 1990; 70:427-51.
3. Wang X, Athayde N, Trudinger B. Microvascular endothelial cell activation is present in the umbilical placental microcirculation in fetal placental vascular disease. Am J Obstet Gynecol 2004 Mar; 190(3):596-601.
4. Patterson TA, Lobenhofer EK, Fulmer-Smentek SB, Collins PJ, Chu TM, et al. Performance comparison of one-color and two-color platforms within the MicroArray Quality Control(MAQC) project. Nat Biotechnol. 2006, 24:1140-1150.
5. Heads RJ, Latchman DS, Yellon DM. Stable high level expression of a transfected human HSP70 gene protects a heart-derived muscle cell line against thermal stress. J Mol Cell Cardiol. 1994; 26:695-699.
6. Cumming DV, Heads RJ, Watson A, Latchman DS, Yellon DM. Differential protection of primary rat cardiocytes by transfection of specific heat shock stress proteins. J Mol Cell Cardiol. 1996; 28:2343-2349.
7. Asea A, Kraeft SK, Kurt-Jones EA, Stevenson MA, Chen LB, Finberg RW, Koo GC, Calderwood SK. HSP70 stimulates cytokine production through a CD14-dependant pathway, demonstrating its dual role as a chaperone and cytokine. Nat Med. 2000; 6:435-442.
8. Srivastava PK, Amato RJ. Heat shock proteins: the "Swiss Army Knife" vaccines against cancers and infectious agents. Vaccine. 2001; 19: 2590-2597.
9. Wendling U, Paul L, van der Zee R, Prakken B, Singh M, van Eden W. A conserved mycobacterial heat shock protein (Hsp) 70 sequence prevents adjuvant arthritis upon nasal administration and induces IL-10- producing T cells that cross-react with the mammalian self-Hsp70 homologue. J Immunol. 2000;164:2711-2717
10. House SD, Guidon PTJ, Perdrizet GA, Rewinski M, Kyriakos R, Bockman RS, Mistry T, Gallagher PA, Hightower LE. Effects of heat shock, stannous chloride, and gallium nitrate on the rat inflammatory response. Cell Stress Chaperones. 2001; 6:164-171.
11. N Thirumoorthy, KT Manisenthil Kumar, A Shyam Sundar, L Panayappan, Malay Chatterjee. Metallothionein: An overview. World J Gastroenterol 2007 February 21; 13(7): 993-996
12. Itoh N, Kimura T. Cytokine-induced metallothionein expression and modulation of cytokine expression by metallothionein. Yakugaku Zasshi. 2007 Apr; 127(4):685-94.
13. Min KS. Physiological significance of metallothionein in oxidative stress. Yakugaku Zasshi. 2007 Apr; 127(4):695-702.
14. Ma HY, Li H, Wang JC, Xu FS. Expression and significance of metallothionein in the placenta of women with low level lead exposure during pregnancy. Zhonghua Fu Chan Ke Za Zhi. 2006 Oct; 41(10):676-9.
15. Peter D, Liu Y , Sternini C , de Giorgio R , Brecha N , Edwards RH . Differential expression of two vesicular monoamine transporters. J Neurosci . 1995 ; 15 : 6179-6188
16. Eiden LE, Schafer MK, Weihe E, Schutz B. The vesicular amine transporter family (SLC 18): amine/proton antiporters required for vesicular accumulation and regulated exocytotic secretion of monoamines and acetylcholine. Pflugers Arch. 2004 Feb; 447(5):636-40.
17. Bottalico B, Larsson I, Brodszki J, Hernandez-Andrade E, Casslen B, Marsal K, Hansson SR. Norepinephrine transporter (NET), serotonin transporter (SERT), vesicular monoamine transporter (VMAT2) and organic cation transporters (OCT1, 2 and EMT) in human placenta from pre-eclamptic and normotensive pregnancies. Placenta. 2004 Jul;25(6):518-29.
18. Sporri B, Kovanen PE, Sasaki A, Yoshimura A, Leonard WJ. JAB/SOCS1/SSI-1 is an interleukin-2-induced inhibitor of IL-2 signaling. Blood. 2001 Jan 1; 97(1):221-6.
19. Bower KE, Zeller RW, Wachsman W, Martinez T, McGuire KL. Correlation of transcriptional repression by p21(SNFT) with changes in DNA.NF-AT complex interactions. J Biol Chem. 2002 Sep 20;277(38):34967-77.
20. Iacobelli M, Wachsman W, McGuire KL. Repression of IL-2 promoter activity by the novel basic leucine zipper p21SNFT protein. J Immunol. 2000 Jul 15; 165(2):860-8.
21. Bower KE, Fritz JM, McGuire KL. Transcriptional repression of MMP-1 by p21SNFT and reduced in vitro invasiveness of hepatocarcinoma cells. Oncogene. 2004 Nov 18;23(54):8805-14.
22. Koutzamani, E., Loborg, H., Sarg, B., Lindner, H. H., and Rundquist, I. (2002) Linker histone subtype composition and affinity for chromatin in situ in nucleated mature erythrocytes. J. Biol. Chem. 277,44688-44694.
23. Parseghian, M. H., and Hamkalo, B. A. A compendium of the histone H1 family of somatic subtypes: an elusive cast of characters and their characteristics. Biochem Cell Biol. 2001;79(3):289-304.
24. Horn, P. J., Carruthers, L. M., Logie, C., Hill, D. A., Solomon, M. J., Wade, P. A., Imbalzano, A. N., Hansen, J. C., and Peterson, C. L. Phosphorylation of linker histones regulates ATP-dependent chromatin remodeling enzymes. Nat. Struct. Biol.2002 Apr;9(4):263-7.
25. Zlatanova, J., and Doenecke, D. Histone H1 zero: a major player in cell differentiation? FASEB J. 1994 Dec; 8(15):1260-8.
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5. Meekins JW, Pijnenborg R, Hanssens M, McFadyen IR, van Asshe A: A study of placental bed spiral arteries and trophoblast invasion in normal and severe pre-eclamptic pregnancies. Br J Obstet Gynaecol 1994, 101:669-674.
6. Aquilina J, Harrington K: Pregnancy hypertension and uterine artery Doppler ultrasound. Curr Opin Obstet Gynecol 1996, 8:435-440
7. Trudinger B, Wang J, Athayde N, Beutler L, Wang X. Association of umbilical placental vascular disease with fetal acute inflammatory cytokine responses. J Soc Gynecol Investig 2002; 9:152-7.
8. Pober JS, Cotran RS. Cytokines and endothelial cell biology. Physiol Rev 1990; 70:427-51.
9. Wang X, Athayde N, Trudinger B. Microvascular endothelial cell activation is present in the umbilical placental microcirculation in fetal placental vascular disease. Am J Obstet Gynecol 2004 Mar; 190(3):596-601.
10. Chen JJ, Wu R, Yang PC, et al. Profiling expression patterns and isolating differentially expressed genes by cDNA microarray system with colorimetydetection. Genomics, 1998, 51(3): 313-324.
11. Patterson TA, Lobenhofer EK, Fulmer-Smentek SB, Collins PJ, Chu TM, et al. Performance comparison of one-color and two-color platforms within the MicroArray Quality Control(MAQC) project. Nat Biotechnol. 2006, 24:1140-1150.
12. Lindquist S, Craig EA. The heat-shock proteins. Amu Rev Genet. 1988.22: 631-677.
13. Heads RJ, Latchman DS, Yellon DM. Stable high level expression of a transfected human HSP70 gene protects a heart-derived muscle cell line against thermal stress. J Mol Cell Cardiol. 1994; 26:695-699.
14. Cumming DV, Heads RJ, Watson A, Latchman DS, Yellon DM. Differential protection of primary rat cardiocytes by transfection of specific heat shock stress proteins. J Mol Cell Cardiol. 1996; 28:2343-2349.
15. Asea A, Kraeft SK, Kurt-Jones EA, Stevenson MA, Chen LB, Finberg RW, Koo GC, Calderwood SK. HSP70 stimulates cytokine production through a CD14-dependant pathway, demonstrating its dual role as a chaperone and cytokine. Nat Med. 2000; 6:435-442.
16. Srivastava PK, Amato RJ. Heat shock proteins: the "Swiss Army Knife" vaccines against cancers and infectious agents. Vaccine. 2001; 19: 2590-2597.
17. Wendling U, Paul L, van der Zee R, Prakken B, Singh M, van Eden W. A conserved mycobacterial heat shock protein (Hsp) 70 sequence prevents adjuvant arthritis upon nasal administration and induces IL-10- producing T cells that cross-react with the mammalian self-Hsp70 homologue. J Immunol. 2000;164:2711-2717
18. House SD, Guidon PTJ, Perdrizet GA, Rewinski M, Kyriakos R, Bockman RS, Mistry T, Gallagher PA, Hightower LE. Effects of heat shock, stannous chloride, and gallium nitrate on the rat inflammatory response. Cell Stress Chaperones. 2001; 6:164-171.
19. Shah M, Stanek J, Handwerger S. Differential localization of heat shock proteins 90, 70, 60 and 27 in human decidua and placenta during pregnancy. Histochem J. 1998 Jul; 30(7):509-18.
20. Asea A, Rehli M, Kabingu E, Boch JA, Bare O, Auron PE, Stevenson MA, Calderwood SK. Novel signal transduction pathway utilized by extracellular HSP70: role of toll-like receptor (TLR) 2 and TLR4. J Biol Chem 2002; 277:15028-15034.
21. Becker T, Hartl FU, Wieland F. CD40, an extracellular receptor for binding and uptake of Hsp70- peptide complexes. J Cell Biol 2002; 158:1277-1285.
22. N Thirumoorthy, KT Manisenthil Kumar, A Shyam Sundar, L Panayappan, Malay Chatterjee. Metallothionein: An overview. World J Gastroenterol 2007 February 21; 13(7): 993-996
23. Itoh N, Kimura T. Cytokine-induced metallothionein expression and modulation of cytokine expression by metallothionein. Yakugaku Zasshi. 2007 Apr; 127(4):685-94.
24. Min KS. Physiological significance of metallothionein in oxidative stress. Yakugaku Zasshi. 2007 Apr; 127(4):695-702.
25. Ma HY, Li H, Wang JC, Xu FS. Expression and significance of metallothionein in the placenta of women with low level lead exposure during pregnancy. Zhonghua Fu Chan Ke Za Zhi. 2006 Oct; 41(10):676-9.
26. Peter D, Liu Y, Sternini C, de Giorgio R, Brecha N, Edwards RH. Differential expression of two vesicular monoamine transporters. J Neurosci. 1995 ; 15 : 6179 -6188.
27. Eiden LE, Schafer MK, Weihe E, Schutz B. The vesicular amine transporter family (SLC18): amine/proton antiporters required for vesicular accumulation and regulated exocytotic secretion of monoamines and acetylcholine. Pflugers Arch. 2004 Feb; 447(5):636-40.
28. Bottalico B, Larsson I, Brodszki J, Hernandez-Andrade E, Casslen B, Marsal K, Hansson SR. Norepinephrine transporter (NET), serotonin transporter (SERT), vesicular monoamine transporter (VMAT2) and organic cation transporters (OCT1, 2 and EMT) in human placenta from pre-eclamptic and normotensive pregnancies. Placenta. 2004 Jul; 25(6):518-29.
29. Sporri B, Kovanen PE, Sasaki A, Yoshimura A, Leonard WJ. JAB/SOCS1/SSI-1 is an interleukin-2-induced inhibitor of IL-2 signaling. Blood. 2001 Jan 1; 97(1):221-6.
30. Bower KE, Zeller RW, Wachsman W, Martinez T, McGuire KL. Correlation of transcriptional repression by p21 (SNFT) with changes in DNA.NF-AT complex interactions. J Biol Chem. 2002 Sep 20; 277(38):34967-77.
31. Iacobelli M, Wachsman W, McGuire KL. Repression of IL-2 promoter activity by the novel basic leucine zipper p21SNFT protein. J Immunol. 2000 Jul 15; 165(2):860-8.
32. Bower KE, Fritz JM, McGuire KL. Transcriptional repression of MMP-1 by p21SNFT and reduced in vitro invasiveness of hepatocarcinoma cells. Oncogene. 2004 Nov 18;23(54):8805-14.
33. Koutzamani, E., Loborg, H., Sarg, B., Lindner, H. H., and Rundquist, I. (2002) Linker histone subtype composition and affinity for chromatin in situ in nucleated mature erythrocytes. J. Biol. Chem. 277,44688-44694.
34. Parseghian, M. H., and Hamkalo, B. A. A compendium of the histone H1 family of somatic subtypes: an elusive cast of characters and their characteristics. Biochem Cell Biol. 2001; 79(3):289-304.
35. Horn, P. J., Carruthers, L. M., Logie, C., Hill, D. A., Solomon, M. J., Wade, P. A., Imbalzano, A. N., Hansen, J. C., and Peterson, C. L. Phosphorylation of linker histones regulates ATP-dependent chromatin remodeling enzymes. Nat. Struct. Biol. 2002 Apr; 9(4):263-7.
36. Zlatanova, J., and Doenecke, D. Histone H1 zero: a major player in cell differentiation? FASEB J. 1994 Dec; 8(15): 1260-8.
1. Meekins JW, Pijnenborg R, Hanssens M, McFadyen IR, van Asshe A: A study of placental bed spiral arteries and trophoblast invasion in normal and severe pre-eclamptic pregnancies. Br J Obstet Gynaecol 1994,101:669-674.
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8. Wang X, Athayde N, Trudinger B. Microvascular endothelial cell activation is present in the umbilical placental microcirculation in fetal placental vascular disease. Am J Obstet Gynecol 2004 Mar; 190(3):596-601.
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14. Asea A, Kraeft SK, Kurt-Jones EA, Stevenson MA, Chen LB, Finberg RW, Koo GC, Calderwood SK. HSP70 stimulates cytokine production through a CD14-dependant pathway, demonstrating its dual role as a chaperone and cytokine. Nat Med 2000; 6:435-442.
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16. Ferns G, Shams S, Shafi S. Heat shock protein 27: its potential role in vascular disease. Int J Exp Pathol. 2006 Aug; 87(4):253-74.
17. Shah M, Stanek J, Handwerger S. Differential localization of heat shock proteins 90, 70, 60 and 27 in human decidua and placenta during pregnancy. Histochem J. 1998 Jul;30(7):509-18.
18. Asea A, Rehli M, Kabingu E, Boch JA, Bare O, Auron PE, Stevenson MA, Calderwood SK. Novel signal transduction pathway utilized by extracellular HSP70: role of toll-like receptor (TLR) 2 and TLR4. J Biol Chem 2002; 277:15028-15034.
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6. Ida, A., Tsuji, Y., Muranaka, J., et al., 2000. IL-18 in pregnancy; the elevation of IL-18 in maternal peripheral blood during labour and complicated pregnancies. J. Reprod. Immunol. 47: 65-74.
7. Pacora, P., Romero, R., Maymon, E., et al., 2000. Participation of the novel cytokine interleukin 18 in the host response to intra-amniotic infection. Am. J. Obstet. Gynecol. 183:1138-1143.
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