重度妊娠高血压综合征胎盘组织细胞凋亡及相关蛋白表达的研究
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摘要
妊娠高血压综合征是妊娠期特有的疾病，主要病变为血管痉挛、血管内皮激活引起的全身多器官的血流灌注不足。其发病率为7-13％，而重度妊高征是导致母婴死亡率上升的重要原因之一。但是其病因不清。
与坏死不同，细胞凋亡是由细胞内部机制引发的主动死亡。人组织细胞凋亡的分子构成十分复杂，涉及与免疫介导相关的细胞外配体、受体——FasL和Fas，以及内源性的死亡信号分子——Bcl-2家族。它们均可激活下游重要的细胞凋亡执行者，caspase级联反应；热休克蛋白70是应激蛋白，有保护细胞的功能，以减少细胞凋亡的发生。
目前，有关正常及异常妊娠胎盘组织细胞凋亡的研究逐渐增多。结果表明，细胞凋亡是胎盘组织老化的正常生理过程之一。在正常妊娠的胎盘组织中可以观察到细胞凋亡现象；而在IUGR等病理妊娠胎盘组织中，其凋亡率升高。同样的，对重度妊高征胎盘组织细胞凋亡的研究有助于深入揭示PIH的发病机制。
目的 观察重度妊高征(SPIH)胎盘组织细胞凋亡现象，研究Bax/Bcl-2、Fas/FasL、Cleaved Caspase-3及热休克蛋白70(HSP70)在胎盘组织细胞
弟。军医大学硕士研究生士文
凋亡中的表达及作用。从胎盘组织细胞凋亡的角度，对妊高征的发病机制
作一初步探讨。
方法 随机选取SPM患者及正常晚孕胎盘组织各30例，用TUNEL、光
镜电镜观察细胞凋亡现象。免疫组化观察 Cleaved Caspase｝、Bax用cl《。
Fas／FasL及 HSP70在正常晚期妊娠及 SPM胎盘组织中的表达，Western blot
检测HSP70在两组之间的表达差异。
结果（l）在晚孕胎盘组织中可见到凋亡细胞，SPth组细胞凋亡发生率
的中位数及四分位数范围为 0．36％（0．20o－0．46％人 正常对照组为 0．15％
m刀9％－O．21％）。二者之间有显著性差异（P＜0刀引。（2）＊8n0在盯m
组与对照组的阳性表达率分别为100％和93％，无显著性差异。但在表达
强度上有明显的差别（P＜0．of）。Western blot的结果显示 HSP70在 SPIH
月盘组织中的表达增强。（）Bax、Fas及 Cleaved Caspase－3的在 SPffe
组的表达有显著的增高。两组中Fas及Bcl－2的表达无显著性差异。
结论 门）SPth胎盘组织细胞凋亡增多与 Baxfficl士、Fas／FasL及 Cleaved
Caspase｝表达的变化有一致性，PIH的发病机制可能与之有关；门）HSP70
不能抑制胎盘细胞凋亡，可能对胎盘的组织细胞有保护调节的作用。（）
本文提出，合体滋养细胞脱落进入母体循环的STBM源自细胞凋亡，而
STBM的增多与妊高征的发病有关。
Pregnancy induced hypertension syndrome is a pregnancy-specific disease of reduced organ perfusion secondary to vasospasm and endothelial activation. It affects 7-13% of all pregnancies, and severe pregnancy induced hypertension syndrome (SPIH) is a major cause of maternal and fetal mortality. But its etiology remains unknown.
Apoptosis differs from necrosis in that the former is an active form of cell death dependent on the internal machinery of the cell. The molecular mechanisms of apoptosis in humans are complex. Those include immune-mediated extracellular ligands and receptors such as the Fas ligand and Fas receptor, and endogenous death signals such as the Bcl-2 family of genes, which converge to activate a central executioner, the caspase cascade. And heat shock protein 70 (HSP70) plays a protective role and increases resistance to apoptosis.
Studies on human placenta! apoptosis in normal and abnormal pregnancies have been continuously growing. These observation can imply that apoptosis may be a normal placental aging process. Apoptosis has been described in placentas of normal human pregnancies and is increased in pregnancies complicated by IUGR, etc. And apoptosis may also has an important role in the placentas of SPIH. This study will be helpful in further understanding the etiology of PEH.
AIM The objective of this study was to determine whether there was an increase in placental apoptosis in pregnancies complicated by SPIH compared with placentas from normal pregnancy. To study the relationship between apoptosis and differential expression of Bax/Bcl-2, Fas/FasL, Cleaved Caspase-3 and HSP70 in placentas of SPIH. To explore the pathogenesis of PIH in placental apoptosis.
METHODS Placental samples were obtained from 30 uncomplicated third-trimester pregnancies and from 30 cases of SPIH. We used terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling staining (TUNEL), light microscopy, electron microscopy to identify and quantify apoptosis. Expression of Fas, Fas ligand, Bcl-2, Bax, Cleaved Caspase-3 and HSP70 was detected by immunohistochemical staining . The expression of HSP70 protein was assessed by Western blot. RESULTS (1) Apoptosis has been conclusively demonstrated within human third-trimester placental tissue. Medians and interquartile ranges of SPIH group was 0.36 % ( 0.20%~0.46% ) ; and the normal control was 0.15% (0.09%~0.21%) . The incidence of apoptosis was higher in placentas of SPIH (P<0.05); (2) The positive rates of HSP70 were 100% in SPIH group and
93% in control, but the intensity of staining was significantly different between these two groups (P<0.01). In comparison to normal control, the expression of HSP70 increased in placentas of SPEH group; (3) Bax, Fas and Cleaved Caspase-3 expression were also significantly greater in the villus trophoblast among the study group compared with controls. There was no difference in the expression of FasL, and Bcl-2 between two groups.
CONCLUSION (1) Increased placental apoptosis and altered expression of Fas/FasL, Bcl-2/Bax and Cleaved Caspase-3 in trophoblast are simultaneous. It might influence pathogenesis of PIH. (2) Expression of HSP70 does not increase resistance to placental apoptosis in SPIH, and it may play a protective role in the pathophysiologic mechanisms of PIH. (3) For the relationship between placental apoptosis and the pathogenesis of PIH, we propose that the process, trophoblast normally sheds STBM (Syncytio- trophoblast microfragments) into maternal circulation, depends on apoptosis. PIH occurs when the burden of STBM is abnormally high.
与坏死不同，细胞凋亡是由细胞内部机制引发的主动死亡。人组织细胞凋亡的分子构成十分复杂，涉及与免疫介导相关的细胞外配体、受体——FasL和Fas，以及内源性的死亡信号分子——Bcl-2家族。它们均可激活下游重要的细胞凋亡执行者，caspase级联反应；热休克蛋白70是应激蛋白，有保护细胞的功能，以减少细胞凋亡的发生。
目前，有关正常及异常妊娠胎盘组织细胞凋亡的研究逐渐增多。结果表明，细胞凋亡是胎盘组织老化的正常生理过程之一。在正常妊娠的胎盘组织中可以观察到细胞凋亡现象；而在IUGR等病理妊娠胎盘组织中，其凋亡率升高。同样的，对重度妊高征胎盘组织细胞凋亡的研究有助于深入揭示PIH的发病机制。
目的 观察重度妊高征(SPIH)胎盘组织细胞凋亡现象，研究Bax/Bcl-2、Fas/FasL、Cleaved Caspase-3及热休克蛋白70(HSP70)在胎盘组织细胞
弟。军医大学硕士研究生士文
凋亡中的表达及作用。从胎盘组织细胞凋亡的角度，对妊高征的发病机制
作一初步探讨。
方法 随机选取SPM患者及正常晚孕胎盘组织各30例，用TUNEL、光
镜电镜观察细胞凋亡现象。免疫组化观察 Cleaved Caspase｝、Bax用cl《。
Fas／FasL及 HSP70在正常晚期妊娠及 SPM胎盘组织中的表达，Western blot
检测HSP70在两组之间的表达差异。
结果（l）在晚孕胎盘组织中可见到凋亡细胞，SPth组细胞凋亡发生率
的中位数及四分位数范围为 0．36％（0．20o－0．46％人 正常对照组为 0．15％
m刀9％－O．21％）。二者之间有显著性差异（P＜0刀引。（2）＊8n0在盯m
组与对照组的阳性表达率分别为100％和93％，无显著性差异。但在表达
强度上有明显的差别（P＜0．of）。Western blot的结果显示 HSP70在 SPIH
月盘组织中的表达增强。（）Bax、Fas及 Cleaved Caspase－3的在 SPffe
组的表达有显著的增高。两组中Fas及Bcl－2的表达无显著性差异。
结论 门）SPth胎盘组织细胞凋亡增多与 Baxfficl士、Fas／FasL及 Cleaved
Caspase｝表达的变化有一致性，PIH的发病机制可能与之有关；门）HSP70
不能抑制胎盘细胞凋亡，可能对胎盘的组织细胞有保护调节的作用。（）
本文提出，合体滋养细胞脱落进入母体循环的STBM源自细胞凋亡，而
STBM的增多与妊高征的发病有关。
Pregnancy induced hypertension syndrome is a pregnancy-specific disease of reduced organ perfusion secondary to vasospasm and endothelial activation. It affects 7-13% of all pregnancies, and severe pregnancy induced hypertension syndrome (SPIH) is a major cause of maternal and fetal mortality. But its etiology remains unknown.
Apoptosis differs from necrosis in that the former is an active form of cell death dependent on the internal machinery of the cell. The molecular mechanisms of apoptosis in humans are complex. Those include immune-mediated extracellular ligands and receptors such as the Fas ligand and Fas receptor, and endogenous death signals such as the Bcl-2 family of genes, which converge to activate a central executioner, the caspase cascade. And heat shock protein 70 (HSP70) plays a protective role and increases resistance to apoptosis.
Studies on human placenta! apoptosis in normal and abnormal pregnancies have been continuously growing. These observation can imply that apoptosis may be a normal placental aging process. Apoptosis has been described in placentas of normal human pregnancies and is increased in pregnancies complicated by IUGR, etc. And apoptosis may also has an important role in the placentas of SPIH. This study will be helpful in further understanding the etiology of PEH.
AIM The objective of this study was to determine whether there was an increase in placental apoptosis in pregnancies complicated by SPIH compared with placentas from normal pregnancy. To study the relationship between apoptosis and differential expression of Bax/Bcl-2, Fas/FasL, Cleaved Caspase-3 and HSP70 in placentas of SPIH. To explore the pathogenesis of PIH in placental apoptosis.
METHODS Placental samples were obtained from 30 uncomplicated third-trimester pregnancies and from 30 cases of SPIH. We used terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling staining (TUNEL), light microscopy, electron microscopy to identify and quantify apoptosis. Expression of Fas, Fas ligand, Bcl-2, Bax, Cleaved Caspase-3 and HSP70 was detected by immunohistochemical staining . The expression of HSP70 protein was assessed by Western blot. RESULTS (1) Apoptosis has been conclusively demonstrated within human third-trimester placental tissue. Medians and interquartile ranges of SPIH group was 0.36 % ( 0.20%~0.46% ) ; and the normal control was 0.15% (0.09%~0.21%) . The incidence of apoptosis was higher in placentas of SPIH (P<0.05); (2) The positive rates of HSP70 were 100% in SPIH group and
93% in control, but the intensity of staining was significantly different between these two groups (P<0.01). In comparison to normal control, the expression of HSP70 increased in placentas of SPEH group; (3) Bax, Fas and Cleaved Caspase-3 expression were also significantly greater in the villus trophoblast among the study group compared with controls. There was no difference in the expression of FasL, and Bcl-2 between two groups.
CONCLUSION (1) Increased placental apoptosis and altered expression of Fas/FasL, Bcl-2/Bax and Cleaved Caspase-3 in trophoblast are simultaneous. It might influence pathogenesis of PIH. (2) Expression of HSP70 does not increase resistance to placental apoptosis in SPIH, and it may play a protective role in the pathophysiologic mechanisms of PIH. (3) For the relationship between placental apoptosis and the pathogenesis of PIH, we propose that the process, trophoblast normally sheds STBM (Syncytio- trophoblast microfragments) into maternal circulation, depends on apoptosis. PIH occurs when the burden of STBM is abnormally high.
引文
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