骨桥蛋白在子痫前期发病机制中作用的研究
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摘要
第一部分骨桥蛋白在正常妊娠与子痫前期胎盘组织中的表达
研究背景子痫前期(preeclampsia,PE)是妊娠期特有的原因不明的多系统疾病,迄今仍然是导致孕产妇及围生儿死亡的重要原因,其发病的中心环节目前认为与滋养细胞侵袭力下降密切相关。细胞外基质的骨桥蛋白(osteopontin, OPN)是一种多功能的细胞因子和黏附蛋白,在介导细胞分化、黏附、增殖与迁移,免疫调节、信号转导、炎症及对感染性疾病的免疫能力等方面有着重要的作用。近年生殖领域的研究表明OPN是影响子宫-胚胎微环境的重要因素,其在滋养细胞、胎盘上都有表达,通过与整合素受体结合,调节绒毛侵入、介导细胞迁移和胎盘形成,参与母胎界面的免疫调节,维持正常妊娠的发生发展。因此我们推测OPN在子痫前期发病机制中发挥重要作用,但其与子痫前期的关系及具体作用机制,国内外均未见报道及研究。
目的研究正常妊娠以及子痫前期患者胎盘组织中OPN mRNA和蛋白表达的不同,探讨OPN与子痫前期的关系。
方法选择正常孕妇20例、子痫前期患者25例(其中轻度子痫前期10例,重度子痫前期15例),采用伊红—苏木素(HE)染色,光镜下观察正常妊娠胎盘结构和子痫前期患者胎盘结构的病理学改变；采用免疫组织化学及Western Blotting方法检测各组孕妇胎盘组织中OPN蛋白定位及定量表达；采用逆转录聚合酶链反应(reverse transcription polymerasechain reaction, RT-PCR)方法检测胎盘组织中的OPN mRNA的表达水平。
结果(数据均为x±s)①光镜下见子痫前期胎盘绒毛肿胀、间质空泡形成及纤维素样坏死发生、合体滋养细胞结节增多、绒毛合体滋养层见大量凋亡细胞,而正常胎盘上述情况极少见；②免疫组化观察分析表明,胎盘组织OPN免疫反应阳性产物主要表达定位于胎盘绒毛滋养细胞的胞浆和胞膜中,并且胎盘毛细血管内皮细胞中也有大量表达；半定量分析结果为：正常晚孕组0.99±0.08,轻度PE组0.63±0.06,重度PE组0.34±0.06；③Western blotting检测各组OPN蛋白结果显示：正常晚孕组1.65±0.11,轻度PE组1.19±0.15,重度PE组0.61±0.10；④RT-PCR检测OPN mRNA结果：正常晚孕组1.01±0.08；轻度PE组0.71±0.07；重度PE组0.39±0.06。结果提示：与正常晚孕组相比,子痫前期胎盘组织中OPN蛋白和mRNA表达显著降低,且与病情严重程度成负相关,即随病情加重其表达进一步降低。
结论OPN在子痫前期患者胎盘组织中的低表达,可能在子痫前期的发病机制中发挥重要作用,并能反应子痫前期病情的严重程度。
第二部分缺氧对滋养细胞骨桥蛋白表达影响的研究
研究背景妊娠早期的母胎界面是一个缺氧的环境,滋养细胞是在相对缺氧的环境里发育生长；OPN在滋养细胞、胎盘上都有表达,在整个妊娠期间介导子宫-胎盘界面的细胞黏附和信号转导作用,调节胚胎滋养层侵袭的深度,以维持正常妊娠的发生发展。子痫前期的临床表现实质上归因于胎盘缺血缺氧后释放各种有毒细胞因子进入母血,导致母体多器官多系统损害,继而出现一系列母体综合征。而体外的研究亦表明缺氧可诱导培养的胎盘出现与子痫前期类似的病变。故本实验拟利用在低氧环境下培养滋养细胞,模拟子痫前期胎盘缺氧的情形,得以在体外进行研究缺氧对滋养细胞OPN表达的影响,以进一步深入研究子痫前期的发病机制。
目的研究缺氧对人胎盘绒毛膜癌滋养细胞系BeWo细胞OPN蛋白及其mRNA表达的影响,从细胞水平研究缺氧对滋养细胞功能的影响,以探求OPN在子痫前期发病机制中的可能作用。
方法采用细胞免疫组化、Western印迹和实时荧光定量PCR检测BeWo细胞在不同氧浓度下OPN蛋白及其mRNA的表达。
结果①在不同氧浓度的环境下,显微镜观察BeWo细胞的生长情况,发现其对缺氧反应敏感,细胞形态发生明显的改变。②细胞免疫组化结果显示：OPN在各组BeWo细胞中均有表达,其免疫反应产物主要表达定位于胞浆和胞膜中；缺氧24小时各组的OPN蛋白表达无明显变化；但缺氧48小时后,低氧组OPN蛋白的表达水平均明显下降,且2%氧组OPN蛋白下降更显著。③Western blotting结果与细胞免疫组化结果一致,但同时用OPN表达阳性的Hela细胞做对照,发现在上述同样缺氧条件下,Hela细胞的OPN表达水平不受影响。④实时荧光定量PCR结果显示：与常氧组相比,8%O2组和2%O2组OPN mRNA表达水平RQ值在缺氧24小时分别为0.7539和0.4833；缺氧48小时后分别为0.5412和0.2140。以上结果表明缺氧对滋养细胞OPN蛋白和mRNA的表达影响呈现出浓度时间依赖性,即随着氧浓度的降低和缺氧时间的延长,OPN表达呈显著下降趋势。但缺氧不影响宫颈癌细胞系Hela细胞OPN的表达。
结论缺氧对BeWo细胞OPN表达降调呈浓度时间依赖性,与子痫前期胎盘组织表达OPN随病情加重进一步降低惊人地相似,推测滋养细胞OPN表达的降低与缺氧导致滋养细胞侵袭力下降密切相关。
第三部分缺氧对滋养细胞侵袭力影响的研究
研究背景妊娠早期滋养细胞有限制的时空特异性侵入子宫壁是人类妊娠得以正常进行的关键。胚胎滋养层细胞发挥类似肿瘤细胞的特性,通过侵入蜕膜再浸润血管内皮完成子宫螺旋动脉的重铸,开启胎盘的血流供应。滋养细胞侵入母体的过程受到多种细胞因子、生长因子、激素和蛋白酶类的调节。在子痫前期患者的胎盘或血液中都有发现这些调节因子表达异常,说明与胎盘缺血缺氧密切相关。第一、第二部分研究结果显示子痫前期胎盘组织OPN表达降低,缺氧亦诱导滋养细胞OPN表达下降,而子痫前期胎盘缺血缺氧普遍存在滋养细胞侵袭力下降,故本研究拟在不同氧浓度环境下,利用Transwell小室模拟子痫前期缺氧环境,体外培养BeWo细胞,进一步研究缺氧对滋养细胞侵袭力的影响。
目的研究缺氧对人绒毛膜癌滋养细胞株BeWo细胞侵袭力的影响,综合分析,探讨OPN与子痫前期滋养细胞侵袭力下降的关系和作用机制。
方法利用气体混配缺氧装置(QT-MTX-3)配置不同氧浓度,模拟子痫前期的发生发展过程,利用Transwell小室和特殊培养基,体外培养BeWo细胞,进一步研究缺氧对滋养细胞侵袭力的影响。
结果显微镜下观察可见各组均有数量不等的BeWo细胞浸润至膜下室,与常氧组相比,8%O2组BeWo细胞浸润指数为0.2988,2%O2组BeWo细胞浸润指数为0.0917,差异显著。结果表明氧浓度愈低BeWo细胞浸润入膜下室的细胞数愈少。
结论缺氧明显抑制BeWo细胞的侵袭力,并随着氧浓度的降低其侵袭力进一步下降。
PartⅠExpression of osteopontin in placental tissues from healthy pregnant women and the patients with preeclampsia
Objective:To study the expression of OPN (osteopontin) in the placental tissues from healthy pregnant women and the patients with preeclampsia, and to explore the relationship between OPN and preeclampsia.
Methods:We obtained 20 cases of placental tissues from healthy pregnant women and 25 cases of those from patients with preeclampsia, including 10 cases of mild preeclampsia,15 cases of severe preeclampsia. First, we observed structure of placental tissues from normal pregnancies and those with preeclampsia after HE (hematoxylin-eosin) staining. Then, we detected OPN expression in the placenta of each group by RT-PCR, Western Blotting and immunohistochemistry.
Results:
1. We found that in preeclampsia placenta, there were villus swelling, interstitial vacuolization, fibrinoid necrosis, nodules increased in syncytiotrophoblast and a large number of apoptotic cells in villous syncytiotrophoblast, which were rare in the normal placenta.
2. Immunohistochemical results showed OPN in placenta were mainly expressed in the cytoplasm and membrane of placental trophoblast cells and also expressed in placental capillary endothelial cells.
3. Western blotting results displayed that relative value of OPN expression in normal late pregnancy group, mild preeclampsia group and severe preeclampsia group was 1.65±0.11, 1.19±0.15 and 0.61±0.10, respectively.
4. RT-PCR results revealed that relative value of OPN mRNA expression in normal late pregnancy group, mild preeclampsia group and severe preeclampsia group was 1.01±0.08, 0.71±0.07 and 0.39±0.06, respectively.
These results suggested that compared with healthy late pregnancy group, OPN expression was significantly decreased in the placental tissues from the patients with preeclampsia, and its expression was negatively related to the severity of preeclampsia.
Conclusion:Low expression of OPN in placenta from preeclampsia patients suggested it would play an important role in the pathogenesis of preeclampsia and be able to reflect the severity of preeclampsia.
PartⅡEffect of hypoxia on the expression of Osteopontin in trophoblast cells
Objective:To investigate the effect of hypoxia on OPN expression in human placental choriocarcinoma trophoblast cell line, BeWo, and to explore the role of OPN in the pathogenesis of preeclampsia.
Methods:Expression of OPN in BeWo cells was measured by real-time PCR, immunohistochemistry and Western boltting under different oxygen concentrations.
Results:
1. The morphology of BeWo cells was obviously changed in hypoxic condition.
2. Immunohistochemical results revealed that OPN was expressed in each group of BeWo cells, which were treated on different oxygen concentration and processing time. OPN was mainly localized in the cytoplasm and membrane of BeWo cells. Moreover, there was no obvious changes of OPN expression after 24 hours hypoxic treatment and its expression significantly decreased after 48 hours hypoxic treatment.
3. The results were consistent with above by Western blotting, but we also found the expression of OPN was not affected in Hela cells, in which OPN was expressed, on the same hypoxic conditions.
4. Real-time PCR results suggested that OPN was expressed in a concentration and time-dependent manner in BeWo cells, which means OPN expression was significantly decreased with reducing oxygen concentration and extending hypoxia time.
Conclusion:OPN was expressed in a concentration and time-dependent manner in BeWo cells after hypoxic treatment, which was the same as decreased OPN expression in preeclampsia placenta with the worsening illness. So we reckoned that decreased expression of OPN was closely related to the invasiveness of trophoblast cells caused by hypoxia.
PartⅢThe effect of hypoxic on the invasiveness of trophoblastic cells
Objective:To study the relationship between hypoxic treatment and invasiveness of BeWo cells and to analyze the relationship between expression of OPN and invasiveness of trophoblast cells in the patients with preeclampsia.
Methods:We simulated preeclampsia process by using an air distributing device (QT-MTX-3), and observed the effects of hypoxic treatment on BeWo invasiveness by using transwell system.
Results:BeWo cells could invase to lower compartment of the transwell system in each group. Comprared to normaxia group, the infiltration index of BeWo cell in 8% O2 group and in 2% O2 group was 0.2988 and 0.0917, respectively. It is suggested that the lower oxygen concentration could decrease the number of BeWo cells which infiltrated into lower compartment.
Conclusion:Hypoxia inhibited the invasion of BeWo cells, which means its invasiveness was conditioned by lower oxygen concentration.
研究背景子痫前期(preeclampsia,PE)是妊娠期特有的原因不明的多系统疾病,迄今仍然是导致孕产妇及围生儿死亡的重要原因,其发病的中心环节目前认为与滋养细胞侵袭力下降密切相关。细胞外基质的骨桥蛋白(osteopontin, OPN)是一种多功能的细胞因子和黏附蛋白,在介导细胞分化、黏附、增殖与迁移,免疫调节、信号转导、炎症及对感染性疾病的免疫能力等方面有着重要的作用。近年生殖领域的研究表明OPN是影响子宫-胚胎微环境的重要因素,其在滋养细胞、胎盘上都有表达,通过与整合素受体结合,调节绒毛侵入、介导细胞迁移和胎盘形成,参与母胎界面的免疫调节,维持正常妊娠的发生发展。因此我们推测OPN在子痫前期发病机制中发挥重要作用,但其与子痫前期的关系及具体作用机制,国内外均未见报道及研究。
目的研究正常妊娠以及子痫前期患者胎盘组织中OPN mRNA和蛋白表达的不同,探讨OPN与子痫前期的关系。
方法选择正常孕妇20例、子痫前期患者25例(其中轻度子痫前期10例,重度子痫前期15例),采用伊红—苏木素(HE)染色,光镜下观察正常妊娠胎盘结构和子痫前期患者胎盘结构的病理学改变；采用免疫组织化学及Western Blotting方法检测各组孕妇胎盘组织中OPN蛋白定位及定量表达；采用逆转录聚合酶链反应(reverse transcription polymerasechain reaction, RT-PCR)方法检测胎盘组织中的OPN mRNA的表达水平。
结果(数据均为x±s)①光镜下见子痫前期胎盘绒毛肿胀、间质空泡形成及纤维素样坏死发生、合体滋养细胞结节增多、绒毛合体滋养层见大量凋亡细胞,而正常胎盘上述情况极少见；②免疫组化观察分析表明,胎盘组织OPN免疫反应阳性产物主要表达定位于胎盘绒毛滋养细胞的胞浆和胞膜中,并且胎盘毛细血管内皮细胞中也有大量表达；半定量分析结果为：正常晚孕组0.99±0.08,轻度PE组0.63±0.06,重度PE组0.34±0.06；③Western blotting检测各组OPN蛋白结果显示：正常晚孕组1.65±0.11,轻度PE组1.19±0.15,重度PE组0.61±0.10；④RT-PCR检测OPN mRNA结果：正常晚孕组1.01±0.08；轻度PE组0.71±0.07；重度PE组0.39±0.06。结果提示：与正常晚孕组相比,子痫前期胎盘组织中OPN蛋白和mRNA表达显著降低,且与病情严重程度成负相关,即随病情加重其表达进一步降低。
结论OPN在子痫前期患者胎盘组织中的低表达,可能在子痫前期的发病机制中发挥重要作用,并能反应子痫前期病情的严重程度。
第二部分缺氧对滋养细胞骨桥蛋白表达影响的研究
研究背景妊娠早期的母胎界面是一个缺氧的环境,滋养细胞是在相对缺氧的环境里发育生长；OPN在滋养细胞、胎盘上都有表达,在整个妊娠期间介导子宫-胎盘界面的细胞黏附和信号转导作用,调节胚胎滋养层侵袭的深度,以维持正常妊娠的发生发展。子痫前期的临床表现实质上归因于胎盘缺血缺氧后释放各种有毒细胞因子进入母血,导致母体多器官多系统损害,继而出现一系列母体综合征。而体外的研究亦表明缺氧可诱导培养的胎盘出现与子痫前期类似的病变。故本实验拟利用在低氧环境下培养滋养细胞,模拟子痫前期胎盘缺氧的情形,得以在体外进行研究缺氧对滋养细胞OPN表达的影响,以进一步深入研究子痫前期的发病机制。
目的研究缺氧对人胎盘绒毛膜癌滋养细胞系BeWo细胞OPN蛋白及其mRNA表达的影响,从细胞水平研究缺氧对滋养细胞功能的影响,以探求OPN在子痫前期发病机制中的可能作用。
方法采用细胞免疫组化、Western印迹和实时荧光定量PCR检测BeWo细胞在不同氧浓度下OPN蛋白及其mRNA的表达。
结果①在不同氧浓度的环境下,显微镜观察BeWo细胞的生长情况,发现其对缺氧反应敏感,细胞形态发生明显的改变。②细胞免疫组化结果显示：OPN在各组BeWo细胞中均有表达,其免疫反应产物主要表达定位于胞浆和胞膜中；缺氧24小时各组的OPN蛋白表达无明显变化；但缺氧48小时后,低氧组OPN蛋白的表达水平均明显下降,且2%氧组OPN蛋白下降更显著。③Western blotting结果与细胞免疫组化结果一致,但同时用OPN表达阳性的Hela细胞做对照,发现在上述同样缺氧条件下,Hela细胞的OPN表达水平不受影响。④实时荧光定量PCR结果显示：与常氧组相比,8%O2组和2%O2组OPN mRNA表达水平RQ值在缺氧24小时分别为0.7539和0.4833；缺氧48小时后分别为0.5412和0.2140。以上结果表明缺氧对滋养细胞OPN蛋白和mRNA的表达影响呈现出浓度时间依赖性,即随着氧浓度的降低和缺氧时间的延长,OPN表达呈显著下降趋势。但缺氧不影响宫颈癌细胞系Hela细胞OPN的表达。
结论缺氧对BeWo细胞OPN表达降调呈浓度时间依赖性,与子痫前期胎盘组织表达OPN随病情加重进一步降低惊人地相似,推测滋养细胞OPN表达的降低与缺氧导致滋养细胞侵袭力下降密切相关。
第三部分缺氧对滋养细胞侵袭力影响的研究
研究背景妊娠早期滋养细胞有限制的时空特异性侵入子宫壁是人类妊娠得以正常进行的关键。胚胎滋养层细胞发挥类似肿瘤细胞的特性,通过侵入蜕膜再浸润血管内皮完成子宫螺旋动脉的重铸,开启胎盘的血流供应。滋养细胞侵入母体的过程受到多种细胞因子、生长因子、激素和蛋白酶类的调节。在子痫前期患者的胎盘或血液中都有发现这些调节因子表达异常,说明与胎盘缺血缺氧密切相关。第一、第二部分研究结果显示子痫前期胎盘组织OPN表达降低,缺氧亦诱导滋养细胞OPN表达下降,而子痫前期胎盘缺血缺氧普遍存在滋养细胞侵袭力下降,故本研究拟在不同氧浓度环境下,利用Transwell小室模拟子痫前期缺氧环境,体外培养BeWo细胞,进一步研究缺氧对滋养细胞侵袭力的影响。
目的研究缺氧对人绒毛膜癌滋养细胞株BeWo细胞侵袭力的影响,综合分析,探讨OPN与子痫前期滋养细胞侵袭力下降的关系和作用机制。
方法利用气体混配缺氧装置(QT-MTX-3)配置不同氧浓度,模拟子痫前期的发生发展过程,利用Transwell小室和特殊培养基,体外培养BeWo细胞,进一步研究缺氧对滋养细胞侵袭力的影响。
结果显微镜下观察可见各组均有数量不等的BeWo细胞浸润至膜下室,与常氧组相比,8%O2组BeWo细胞浸润指数为0.2988,2%O2组BeWo细胞浸润指数为0.0917,差异显著。结果表明氧浓度愈低BeWo细胞浸润入膜下室的细胞数愈少。
结论缺氧明显抑制BeWo细胞的侵袭力,并随着氧浓度的降低其侵袭力进一步下降。
PartⅠExpression of osteopontin in placental tissues from healthy pregnant women and the patients with preeclampsia
Objective:To study the expression of OPN (osteopontin) in the placental tissues from healthy pregnant women and the patients with preeclampsia, and to explore the relationship between OPN and preeclampsia.
Methods:We obtained 20 cases of placental tissues from healthy pregnant women and 25 cases of those from patients with preeclampsia, including 10 cases of mild preeclampsia,15 cases of severe preeclampsia. First, we observed structure of placental tissues from normal pregnancies and those with preeclampsia after HE (hematoxylin-eosin) staining. Then, we detected OPN expression in the placenta of each group by RT-PCR, Western Blotting and immunohistochemistry.
Results:
1. We found that in preeclampsia placenta, there were villus swelling, interstitial vacuolization, fibrinoid necrosis, nodules increased in syncytiotrophoblast and a large number of apoptotic cells in villous syncytiotrophoblast, which were rare in the normal placenta.
2. Immunohistochemical results showed OPN in placenta were mainly expressed in the cytoplasm and membrane of placental trophoblast cells and also expressed in placental capillary endothelial cells.
3. Western blotting results displayed that relative value of OPN expression in normal late pregnancy group, mild preeclampsia group and severe preeclampsia group was 1.65±0.11, 1.19±0.15 and 0.61±0.10, respectively.
4. RT-PCR results revealed that relative value of OPN mRNA expression in normal late pregnancy group, mild preeclampsia group and severe preeclampsia group was 1.01±0.08, 0.71±0.07 and 0.39±0.06, respectively.
These results suggested that compared with healthy late pregnancy group, OPN expression was significantly decreased in the placental tissues from the patients with preeclampsia, and its expression was negatively related to the severity of preeclampsia.
Conclusion:Low expression of OPN in placenta from preeclampsia patients suggested it would play an important role in the pathogenesis of preeclampsia and be able to reflect the severity of preeclampsia.
PartⅡEffect of hypoxia on the expression of Osteopontin in trophoblast cells
Objective:To investigate the effect of hypoxia on OPN expression in human placental choriocarcinoma trophoblast cell line, BeWo, and to explore the role of OPN in the pathogenesis of preeclampsia.
Methods:Expression of OPN in BeWo cells was measured by real-time PCR, immunohistochemistry and Western boltting under different oxygen concentrations.
Results:
1. The morphology of BeWo cells was obviously changed in hypoxic condition.
2. Immunohistochemical results revealed that OPN was expressed in each group of BeWo cells, which were treated on different oxygen concentration and processing time. OPN was mainly localized in the cytoplasm and membrane of BeWo cells. Moreover, there was no obvious changes of OPN expression after 24 hours hypoxic treatment and its expression significantly decreased after 48 hours hypoxic treatment.
3. The results were consistent with above by Western blotting, but we also found the expression of OPN was not affected in Hela cells, in which OPN was expressed, on the same hypoxic conditions.
4. Real-time PCR results suggested that OPN was expressed in a concentration and time-dependent manner in BeWo cells, which means OPN expression was significantly decreased with reducing oxygen concentration and extending hypoxia time.
Conclusion:OPN was expressed in a concentration and time-dependent manner in BeWo cells after hypoxic treatment, which was the same as decreased OPN expression in preeclampsia placenta with the worsening illness. So we reckoned that decreased expression of OPN was closely related to the invasiveness of trophoblast cells caused by hypoxia.
PartⅢThe effect of hypoxic on the invasiveness of trophoblastic cells
Objective:To study the relationship between hypoxic treatment and invasiveness of BeWo cells and to analyze the relationship between expression of OPN and invasiveness of trophoblast cells in the patients with preeclampsia.
Methods:We simulated preeclampsia process by using an air distributing device (QT-MTX-3), and observed the effects of hypoxic treatment on BeWo invasiveness by using transwell system.
Results:BeWo cells could invase to lower compartment of the transwell system in each group. Comprared to normaxia group, the infiltration index of BeWo cell in 8% O2 group and in 2% O2 group was 0.2988 and 0.0917, respectively. It is suggested that the lower oxygen concentration could decrease the number of BeWo cells which infiltrated into lower compartment.
Conclusion:Hypoxia inhibited the invasion of BeWo cells, which means its invasiveness was conditioned by lower oxygen concentration.
引文
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27. Johnson GA, Burghardt RC, Bazer FW, et al. Osteopontin:roles in implantation and placentation [J]. Biol Reprod,2003,69(5):1458-1471.
28.王雁玲.胎盘植入障碍与先兆子痫[J].医学分子生物学杂志,2003,3(2)：85-89.
29. Redman CW, Sargent IL. Latest advances in understanding preeclampsia[J]. Science, 2005,308(5728):1592-1594.
30. Sibai B, Dekker G, Kupferminc M. Pre-eclampsia[J]. Lancet,2005, 365(9461):785-799.
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32. Gabinskaya T, Salafia CM, Gulle VE,et al.Gestational age-dependent extravillous cytotrophoblast osteopontin immunolocalization differentiates between normal and
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