子痫前期孕妇胎盘和血清中氧化应激损伤与滋养细胞人类白细胞相关性抗原G表达的相互影响
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摘要
研究目的：
子痫前期是孕产妇和围产儿发病及死亡的重要原因。对其发病机制的研究一直是产科关注的热点。以人白细胞相关性抗原-G（HLA-G）表达下降为代表的免疫学说是子痫前期的经典病因，而以过氧化氢（H_2O_2）水平升高为特点的氧化应激学说亦是近年来其发病机制的重大进展，二者有无相关性，是否有潜在因果联系尚不明确。本研究将从分子生物学，细胞生物学等方面进一步探究：子痫前期胎盘和血清中过度氧化应激与滋养细胞上HLA-G表达有无相关性及表达HLA-G阳性的滋养细胞是否更容易受到氧化应激损伤。
研究方法：
1.（1）选择2008年10月-2009年10月南京医科大学第一附属医院住院产妇60例，其中正常妊娠组和子痫前期组各30例。采用比色法检测子痫前期和正常妊娠组胎盘组织中H_2O_2水平；采用免疫组化、Western Blot检测两组胎盘组织中HLA-G蛋白的表达水平；并对胎盘组织中H_2O_2水平与HLA-G蛋白表达水平进行相关性分析。（2）H_2O_2干预0h、24h、48h后，免疫荧光法和Western Blot分析滋养细胞株HTR-8/SVneo上HLA-G表达量变化。
2.（1）选择2010年6月-2010年12月南京医科大学第一附属医院发生重度子痫前期住院分娩产妇30例，其中早发型子痫前期组及晚发型子痫前期组各15例；选择门诊建卡晚孕产检的正常孕妇15例。采用比色法检测早发型子痫前期、晚发型子痫前期和正常妊娠组血清中H_2O_2水平；采用ELISA法检测三组孕妇血清中sHLA-G蛋白的表达水平；并对三组孕妇血清中H_2O_2水平与sHLA-G蛋白表达水平进行相关性分析（。2）H_2O_2干预0h、24h、48h后，ELISA法分析HTR-8/SVneo细胞上清中sHLA-G表达量变化。
3.（1） HLA-G siRNA和control siRNA寡聚核苷酸转染滋养细胞株HTR-8/SVneo，并采用Western Blot和RT-PCR验证干扰效果。（2）H_2O_2干预后，采用MTT法检测转染细胞的增殖能力；流式检测转染细胞的凋亡率；Transwell实验检测转染细胞的侵袭能力；明胶酶谱检测转染细胞侵袭相关蛋白MMP-2、MMP-9的活性改变。
研究结果：
1.（1）和正常产妇相比，子痫前期产妇胎盘组织中H_2O_2含量呈高表达，HLA-G蛋白呈低表达，并且H_2O_2含量和HLA-G的表达量呈负相关；(2)H_2O_2干预HTR-8/SVneo细胞后，干预组HLA-G蛋白表达量明显低于空白组，并且随着时间的延长而降低；荧光显微镜显示，干预组细胞中HLA-G表达强度亦明显弱于对照组。
2.（2）正常妊娠组、晚发型及早发型重度子痫前期孕妇血清中H_2O_2含量逐渐升高，sHLA-G蛋白表达量逐渐降低，并且H_2O_2含量和sHLA-G蛋白表达量呈负相关（2）H_2O_2干预HTR-8/SVneo细胞0h、24h、48h后，干预组sHLA-G分泌量明显低于空白组，并且随着时间的延长而降低。
3. H_2O_2干预后，和HLA-G siRNA组相比，control siRNA组细胞的增殖抑制率和凋亡率增高，侵袭能力和侵袭相关蛋白MMP-2、MMP-9的活性明显下降。
研究结论：
1.子痫前期中，高水平的H_2O_2会下调滋养细胞上HLA-G（包括sHLA-G）的表达。
2.表达HLA-G的滋养细胞更容易受到氧化应激损伤。
Objective: Preeclampsia (PE) is a major contributor to maternal and neonatalmortality and morbidity and the precise etiology of PE is still open to debate. Inparticular, oxidative stress and immune maladaptation seem to attract people’sattention in the development of PE. The aim of this study was to investigate apossible association between Hydrogen peroxide (H_2O_2) and leukocyte antigen-G(HLA–G) expressed by trophoblasts in maternal placenta and serum duringpreeclampsia.
Methods:
1.(1)Sixty pregnant women, delivered through cesarean section in theDepartment of Obstetrics of and Gynecology, the First Affiliated Hospital ofNanjing Medical University from October2008to October2009, wereenrolled, including30women with preeclampsia and30healthy gravidas(control group). Colorimetry was applied to determine the level of H_2O_2ofplacental tissues. Immunohistochemistry and western blot were used todetermine the relative expression of HLA-G protein in placental tissues. Thecorrelation between H_2O_2level and HLA-G protein expression was analyzed.(2)Immunofluorese and western blot were used to investigate the expressionof HLA-G protein in HTR-8/SVneo cells after incubation with H_2O_2for0h、 24h、48h.
2.(1)Blood samplings of15women diagnosed early-onset preeclampsia,15women diagnosed later-onset preeclampsia and15healthy women (controlgroup) at term in the Department of Obstetrics of and Gynecology, the FirstAffiliated Hospital of Nanjing Medical University from June2010toDecember2010were collected. Colorimetry and ELISA were applied,respectively, to determine the level of H_2O_2and the expression of sHLA-Gprotein in maternal serum and the correlation between them were analyzed.(2)ELISA was used to investigate the expression of sHLA-G protein inHTR-8/SVneo cell supernatant after incubation with H_2O_2for0h、24h、48h.
3.(1)HTR-8/SVneo cells were transfected with HLA-G siRNA and controlsiRNA oligofectamine and the effect was analyzed by RT-PCR and Westernblot.(2) Effects of HLA-G on the proliferation, apoptosis and invasion ofHTR-8/SVneo cells when exposed to H_2O_2were evaluated via MTT assay,Flow cytometric mothod, Transwell assay and Gelatin enzyme, respectively.
Results:
1. Compared with control group, higher level of H_2O_2and lower relativeexpression of HLA-G protein were found in preeclamptic placentas and therewas an inverse correlation between HLA-G and H_2O_2levels in the twogroups.(2) Compared to the relative expression of HLA-G protein in thecontrol group, the relative expression of HLA-G in HTR-8/SVneo cells afterexposure to H_2O_2was reduced with time-dependent. Reduced expression ofHLA-G was also observed in HTR-8/SVneo cells by fluorescence microscopein the intervention group compared to the control group.
2. Compared with control goup, the concentration of H_2O_2was higher inearly-onset preeclampsia and later-onset preeclampsia serum. The concentration of serum H_2O_2was higher in early-onset preeclampsia thanlater-onset preeclampsia. Compared with control goup, the expression ofsHLA-G was decreased in early-onset preeclampsia and later-onsetpreeclampsia serum. The expression of serum sHLA-G was decreased inearly-onset preeclampsia than later-onset preeclampsia. There was an inversecorrelation between HLA-G and H_2O_2at term in the maternal serum.(2)Compared with control group, the expression of sHLA-G in the supernatantof cells exposed to H_2O_2was reduced with time-dependent.
3. Compared with HLA-G knockdown HTR-8/SVneo, increased proliferationinhibition, higher apoptosis and decreased cell invasion were found in the cellexpressing HLA-G when exposed to H_2O_2.
Conclusion：Our findings highlight that high levels of H_2O_2can down-regulateHLA-G protein (including sHLA-G) expression in trophoblasts during preeclampsiaand trophoblasts expressing HLA-G are vulnerable to oxidative stress.
子痫前期是孕产妇和围产儿发病及死亡的重要原因。对其发病机制的研究一直是产科关注的热点。以人白细胞相关性抗原-G（HLA-G）表达下降为代表的免疫学说是子痫前期的经典病因，而以过氧化氢（H_2O_2）水平升高为特点的氧化应激学说亦是近年来其发病机制的重大进展，二者有无相关性，是否有潜在因果联系尚不明确。本研究将从分子生物学，细胞生物学等方面进一步探究：子痫前期胎盘和血清中过度氧化应激与滋养细胞上HLA-G表达有无相关性及表达HLA-G阳性的滋养细胞是否更容易受到氧化应激损伤。
研究方法：
1.（1）选择2008年10月-2009年10月南京医科大学第一附属医院住院产妇60例，其中正常妊娠组和子痫前期组各30例。采用比色法检测子痫前期和正常妊娠组胎盘组织中H_2O_2水平；采用免疫组化、Western Blot检测两组胎盘组织中HLA-G蛋白的表达水平；并对胎盘组织中H_2O_2水平与HLA-G蛋白表达水平进行相关性分析。（2）H_2O_2干预0h、24h、48h后，免疫荧光法和Western Blot分析滋养细胞株HTR-8/SVneo上HLA-G表达量变化。
2.（1）选择2010年6月-2010年12月南京医科大学第一附属医院发生重度子痫前期住院分娩产妇30例，其中早发型子痫前期组及晚发型子痫前期组各15例；选择门诊建卡晚孕产检的正常孕妇15例。采用比色法检测早发型子痫前期、晚发型子痫前期和正常妊娠组血清中H_2O_2水平；采用ELISA法检测三组孕妇血清中sHLA-G蛋白的表达水平；并对三组孕妇血清中H_2O_2水平与sHLA-G蛋白表达水平进行相关性分析（。2）H_2O_2干预0h、24h、48h后，ELISA法分析HTR-8/SVneo细胞上清中sHLA-G表达量变化。
3.（1） HLA-G siRNA和control siRNA寡聚核苷酸转染滋养细胞株HTR-8/SVneo，并采用Western Blot和RT-PCR验证干扰效果。（2）H_2O_2干预后，采用MTT法检测转染细胞的增殖能力；流式检测转染细胞的凋亡率；Transwell实验检测转染细胞的侵袭能力；明胶酶谱检测转染细胞侵袭相关蛋白MMP-2、MMP-9的活性改变。
研究结果：
1.（1）和正常产妇相比，子痫前期产妇胎盘组织中H_2O_2含量呈高表达，HLA-G蛋白呈低表达，并且H_2O_2含量和HLA-G的表达量呈负相关；(2)H_2O_2干预HTR-8/SVneo细胞后，干预组HLA-G蛋白表达量明显低于空白组，并且随着时间的延长而降低；荧光显微镜显示，干预组细胞中HLA-G表达强度亦明显弱于对照组。
2.（2）正常妊娠组、晚发型及早发型重度子痫前期孕妇血清中H_2O_2含量逐渐升高，sHLA-G蛋白表达量逐渐降低，并且H_2O_2含量和sHLA-G蛋白表达量呈负相关（2）H_2O_2干预HTR-8/SVneo细胞0h、24h、48h后，干预组sHLA-G分泌量明显低于空白组，并且随着时间的延长而降低。
3. H_2O_2干预后，和HLA-G siRNA组相比，control siRNA组细胞的增殖抑制率和凋亡率增高，侵袭能力和侵袭相关蛋白MMP-2、MMP-9的活性明显下降。
研究结论：
1.子痫前期中，高水平的H_2O_2会下调滋养细胞上HLA-G（包括sHLA-G）的表达。
2.表达HLA-G的滋养细胞更容易受到氧化应激损伤。
Objective: Preeclampsia (PE) is a major contributor to maternal and neonatalmortality and morbidity and the precise etiology of PE is still open to debate. Inparticular, oxidative stress and immune maladaptation seem to attract people’sattention in the development of PE. The aim of this study was to investigate apossible association between Hydrogen peroxide (H_2O_2) and leukocyte antigen-G(HLA–G) expressed by trophoblasts in maternal placenta and serum duringpreeclampsia.
Methods:
1.(1)Sixty pregnant women, delivered through cesarean section in theDepartment of Obstetrics of and Gynecology, the First Affiliated Hospital ofNanjing Medical University from October2008to October2009, wereenrolled, including30women with preeclampsia and30healthy gravidas(control group). Colorimetry was applied to determine the level of H_2O_2ofplacental tissues. Immunohistochemistry and western blot were used todetermine the relative expression of HLA-G protein in placental tissues. Thecorrelation between H_2O_2level and HLA-G protein expression was analyzed.(2)Immunofluorese and western blot were used to investigate the expressionof HLA-G protein in HTR-8/SVneo cells after incubation with H_2O_2for0h、 24h、48h.
2.(1)Blood samplings of15women diagnosed early-onset preeclampsia,15women diagnosed later-onset preeclampsia and15healthy women (controlgroup) at term in the Department of Obstetrics of and Gynecology, the FirstAffiliated Hospital of Nanjing Medical University from June2010toDecember2010were collected. Colorimetry and ELISA were applied,respectively, to determine the level of H_2O_2and the expression of sHLA-Gprotein in maternal serum and the correlation between them were analyzed.(2)ELISA was used to investigate the expression of sHLA-G protein inHTR-8/SVneo cell supernatant after incubation with H_2O_2for0h、24h、48h.
3.(1)HTR-8/SVneo cells were transfected with HLA-G siRNA and controlsiRNA oligofectamine and the effect was analyzed by RT-PCR and Westernblot.(2) Effects of HLA-G on the proliferation, apoptosis and invasion ofHTR-8/SVneo cells when exposed to H_2O_2were evaluated via MTT assay,Flow cytometric mothod, Transwell assay and Gelatin enzyme, respectively.
Results:
1. Compared with control group, higher level of H_2O_2and lower relativeexpression of HLA-G protein were found in preeclamptic placentas and therewas an inverse correlation between HLA-G and H_2O_2levels in the twogroups.(2) Compared to the relative expression of HLA-G protein in thecontrol group, the relative expression of HLA-G in HTR-8/SVneo cells afterexposure to H_2O_2was reduced with time-dependent. Reduced expression ofHLA-G was also observed in HTR-8/SVneo cells by fluorescence microscopein the intervention group compared to the control group.
2. Compared with control goup, the concentration of H_2O_2was higher inearly-onset preeclampsia and later-onset preeclampsia serum. The concentration of serum H_2O_2was higher in early-onset preeclampsia thanlater-onset preeclampsia. Compared with control goup, the expression ofsHLA-G was decreased in early-onset preeclampsia and later-onsetpreeclampsia serum. The expression of serum sHLA-G was decreased inearly-onset preeclampsia than later-onset preeclampsia. There was an inversecorrelation between HLA-G and H_2O_2at term in the maternal serum.(2)Compared with control group, the expression of sHLA-G in the supernatantof cells exposed to H_2O_2was reduced with time-dependent.
3. Compared with HLA-G knockdown HTR-8/SVneo, increased proliferationinhibition, higher apoptosis and decreased cell invasion were found in the cellexpressing HLA-G when exposed to H_2O_2.
Conclusion：Our findings highlight that high levels of H_2O_2can down-regulateHLA-G protein (including sHLA-G) expression in trophoblasts during preeclampsiaand trophoblasts expressing HLA-G are vulnerable to oxidative stress.
引文
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13. Fons P, Chabot S, Cartwright JE, et al. Soluble HLA-G1inhibits angiogenesisthrough an apoptotic pathway and by direct binding to CD160receptor expressedby endothelial cells. Blood,2006,108:2608-2615.
14. Steinborn A, Varkonyi T scharf A.Early detection of decreased soluble HLA-Glevels in the maternal circulation predicts the occurrence of preeclampsia andintrauterine growth retardation during further course of pregnancy [J].Am JReprod Immunol,2007,57(4):277-286.
15. Eric Jauniaux, Lucilla Poston, and Graham J. Burton. Placental-related diseasesof pregnancy: involvement of oxidative stress and implications in humanevolution. Hum Reprod Update,2006,12(6):747–755.
16. Lockwood cJ, Toti P, Areuri F, et a1.Thrombin regulates soluble fms-liketyrosine kinase-1(sFlt-1) expression in first trimester decidua: implications forpreelampsia [J]. Int J Fertil Womens Med,2007,52(2-3):59-67.
1. Shido F, Ito T, Nomura S, Yamamoto E, Sumigama S, Ino K, et al. Endoplasmicreticulum aminopeptidase-1mediates leukemia inhibitory factor-induced cellsurface human leukocyte antigen-G expression in JEG-3choriocarcinoma cells.Endocrinology,2006,147:1780-8.
2. Catherine Menier, Berta Saez, Vaclav Horejsi, Silvia Martinozzi, IreneKrawice-Radanne, et al. Characterization of Monoclonal Antibodies RecognizingHLA-G or HLA-E: New Tools to Analyze the Expression of Nonclassical HLAClass I Molecules. Human Immunology,2003,64:315–326.
3. Urosevic M，Kurrer MO，Kamarashev J，et al. Human leukocyte antigen Gup-regulation in lung cancer associates with high-grade histology， humanleukocyte antigen class I loss and interleukin-10production. Am J Pathol,2001，159：817-824.
4. Ishitani A, Sageshima N, Lee N, Dorofeeva N, Hatake K, Marquardt H, et al.Protein expression and peptide binding suggest unique and interact-ing functionalroles for HLA-E, F and G in maternal–placental immune recognition. J Immunol,2003,171:1376–8.
5. Kharfi A, Gigue`re Y, De Grandpre′P, Moutquin JM, Forest JC. Humanchorionic gonadotropin (hCG) may be a marker of systemic oxidative stress innormo-tensive and preeclamptic term pregnancies. Clin Biochem,2005,38(8):717–21.
6.孙丽洲，杨娜娜．重度子痫前期患者胎盘滋养细胞凋亡现象的研究．南京医科大学学报：自然科学版，2007，27：1436-1439。
7. Symonds, H., Krall, L., Remington, L., Saenz-Robles, M., Lowe, S., Jacks, T.&Van Dyke, T. p53-dependent apoptosis suppresses tumor growth and progressionin vivo. Cell,1994,78:703-711.
8. Lowe, S. W., Bodis, S., McClatchey, A., Remington, L., Ruley, H. E., Fisher, D.E., Housman, D.E.&Jacks, T. p53status and the efficacy of cancer therapy invivo. Science,1994,266:807-810.
9. Ross, R. The pathogenesis of atherosclerosis: a perspective for the1990s. Nature,1993,362:801-809.
10. Cindrova-Davies T. Gabor than award lecture2008preeclampsia from placentaloxidative stress to maternal endothelial dysfunction. Placenta,2009,30:55-65.
11. T M Johnson, Z X Yu, V J Ferrans, R A Lowenstein, and T Finkel. Reactiveoxygen species are downstream mediators of p53-dependent apoptosis. Proc. Natl.Acad. Sci.1996,93:11848-11852.
12. Eric Jauniaux, Lucilla Poston, Graham J.Burton.Placental-related diseases ofpregnancy: involvement of oxidative stress and implications in human evolution.Human Reproduction Update,2006,12:747–755.
13. Sudjit Luanpitpong, Siera Jo Talbott, Yon Rojanasakul, Ubonthip Nimmannit‖,Varisa Pongrakhananon, Liying Wang and Pithi Chanvorachote. Regulation ofLung Cancer Cell Migration and Invasion by Reactive Oxygen Species andCaveolin-1. Biol Chem.,2010,285(50):38832-40.
14. Huang X, Huang H, Dong M, Yao Q, Wang H. Serum and placental interleukin-18are elevated in preeclampsia. J Reprod Immunol,2005,65:77–87.
1. Boyd JD, Hamilton WJ, Boyd CA. The surface of the syncytium of the humanchorionic villus. J Anat,1968,102(Pt3):553-63.
2. Kaufmann P and Burton GJ. Anatomy and genesis of the placenta. ThePhysiology of Reproduction,1994,2:441–484.
3. Jauniaux E, Gulbis B,Burton GJ. The human first trimester gestational sac limitsrather than facilities oxygen transfer to the foetus: a review. Placenta-Trophoblast,2003,24:86–93.
4. Jauniaux E and Gulbis B. Fluid compartments of the embryonic environment.Human Reprod Update,2000,6:268–278.
5. Ezashi T, Das P, Roberts RM. Low O2tensions and the prevention of hES cells.Proc Natl Acad Sci USA,2005,102:4783–4788.
6. Jauniaux E, Watson AL, Hempstock J, et al. Onset of maternal arterial bloodflow and placental oxidative stress: a possible factor in human early pregnancyfailure. Am J Pathol,2000,157:2111–2122.
7. Xing Y, Williams C, Campbell RK, et al.Threading of a glycosylated protein loopthrough a protein hole: implications for combination of human chorionicgonadotropin subunits. Protein Sci,2001,10:226–235.
8. Mendelson CR, Jiang B, Shelton JM, et al. Transcriptional regulation ofaromatase in placenta and ovary. J Steroid Biochem Mol Biol,2005,95:25–33.
9. Martin CB, McGaughey HS, Kaiser IH, et al. Intermittent functioning of theuteroplacental arteries. Am J Obstet Gynecol,1964,90:819–823.
10. Hung TH, Skepper JN, Burton G. In vitro ischemia-reperfusion injury in termhuman placenta as a model for oxidative stress in pathological pregnancies. Am JPathol,2001,159:1031–1043.
11. Vanderlie J, Venardos K, Clifton VL, et al.Increased biological oxidation andreduced anti-oxidant enzyme activity in pre-eclamptic placentae. Placenta,2005,26:53–58.
12. Lorentzen B, Endersen MJ, Clausen T,et al. Fasting serum free fatty acids andtriglycerides are increased before20weeks of gestation in women who laterdevelop preeclampsia. Hypertens Pregnancy,1994,13:103–109.
13. Chappell LC, Seed PT, Kelly FJ, et al. Vitamin C and E supplementation inwomen at risk of preeclampsia is associated with changes in indices of oxidativestress and placental function. Am J Obstet Gynecol,2002,187:777–784.
14. Einarsson JL, Sangi-Haghpeykar H, Gardner MO.Sperm exposure anddevelopment of preeclampsia. Am J Obstet Gynecol,2003,188:1241–1243.
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16. Moore S, Ide M, Coward PY, et al. A prospective study to investigate therelationship between periodontal disease and adverse pregnancy outcome. BrDent J,2004,197:251–258.
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19. Jauniaux E, Burton GJ.Pathophysiology of histological changes in earlypregnancy loss. Placenta,2005,26:114–123.
20. Hempstock J, Jauniaux E, Greenwold N，et al. The contribution of placentaloxidative stress to early pregnancy failure. Hum Pathol,2003,34:1265–1275.
21. Aydan Biri, Mustafa Kavutcu. Nuray Bozkurtnvestigation of Free RadicalScavenging Enzyme Activities and Lipid Peroxidation in Human PlacentalTissues with Miscarriage.Journal of the Society for Gynecologic Investigation,2006,13:384-388.
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24.石春燕，孙丽洲，德伟。子痫前期患者胎盘组织氧化应激与PeroxiredoxinII。现代妇产科进展，2008，17(12)：929-931.
25.李颖,陈琪玮。谷肤甘肤治疗中度妊高征对机体抗氧化系统及新生儿窒息影响的研究。中国优生与遗传杂志，2006，14（2）：40-41.
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2. Joan SH, Margaret G Petroff, Ramsey HM,et al. HLA-G and immune tolerancein pregnancy.FASEBJ,2005,19:681-69.
3. Creput C, Durrbach A, Menier C, Guettier C, Samuel D, Dausset J, CharpentierB, Carosella ED and Rouas-Freiss N Human leukocyte antigen-G (HLA-G)expression in biliary epithelial cells is associated with allograft acceptance inliver-kidney transplantation. J Hepatol,2003,39:587–594.
4. Shang-mian Yie, Rong Xiao and Clifford L.Librach Progesterone regulatesHLA-G gene expression through a novel progesterone response element.HumanReproduction,2006,21(10):2538–2544.
5.王炎秋,邢福祺,陈士岭.甾体激素对绒毛外滋养细胞表达HLA-G蛋白的影响.生殖与避孕,200,27(4):260-263.
6. Laura Menendez, L DeEtte Walker, Lilya Matyunina, et al. Epigenetic changeswithin the promoter region of the HLA-G genein ovarian tumors. MlolecularCancer,2008, doi:10.1186/1476-4598-7-43.
7. Yie SM, Xiao R&Librach CL. Progesterone regulates HLA-G gene expressionthrough a novel progesterone response element. Human Reproduction,2006,21(10):2538–2544.
8.张文权,熊文琴,彭国庆.孕酮对早孕人滋养层HLA-G mRNA转录水平的调控.生殖与避孕,2005,25(7):400-402.
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13. Sandra V. Ashton, Guy St. J. Whitley, Philip R. Dash.Uterine Spiral ArteryRemodeling Involves Endothelial Apoptosis Induced by ExtravillousTrophoblasts Through Fas/FasL Interactions.Arteri-oscler. Thromb. Vasc. Biol.2005,25:102-108.
14. Pierre Fons, Sophie Chabot, Judith E.Soluble HLA-G1inhibits angiogenesisthrough an apoptotic pathway and by direct binding to CD160receptor expressedby endothelial cells.Blood,2006,108:2608-2615.
15. Olimpia Sipak-Szmigiel, El bieta Ronin-Walknowska, Cezary Cybulski. AntigensHLA-G, sHLA-G and sHLA-class in reproductive failure.FOLIAHISTOCHEMICA ET CYTOBIOLOGICA,2007,45(1):137-144.
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18. Ga l Mouillot, Céline Marcou, Inès Zidi, Christine Guillard.Hypoxia ModulatesHLA-G Gene Expression in Tumor Cells.Human Immunology,2007,68:277–285.
19.张玲.正常妊娠与子病前期的免疫调节.J Int Repord Health/Fam Plan,2007,27(1):27-30.
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21.王飞,李辉,温泽清,HLA-G与肿瘤细胞的免疫逃逸.中华肿瘤防治杂志,2007,14(22):1751-1754.
22. Nermine Lila, Catherine Amerin, Romain Guillemain, et al. Human leukocyteantigen-G expression after heart transplantation is associated with a reducedincidence of rejection. Circulation,2002,105(16):1949-54.
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2. Martin CB, McGaughey HS, Kaiser IH, et al. Intermittent functioning of theuteroplacental arteries. Am J Obstet Gynecol,1964,90:819–823.
3. Huang TH, Skepper JN, Burton GJ. In vitro ischemia-reperfusion injury in termhuman placenta as a model for oxidative stress in pathological pregnancies. AmJ Pathol,2001,159:1031-1043.
4. Cindrova-Davies T. Gabor than award lecture2008: pre-eclampsia-fromplacental oxidative stress to maternal endothelial dysfunction. Placenta,2009,30（SupplA）:S55-65.
5.孙丽洲,杨娜娜.重度子痫前期患者胎盘滋养细胞凋亡现象的研究.南京医科大学学报(自然科学版),2007,27:1436-1439。
6. A. Aris, S. Benali, A. Ouellet,et al. Potential Biomarkers of Preeclampsia: InverseCorrelation between Hydrogen Peroxide and Nitric Oxide Early in MaternalCirculation and at Term in Placenta of Women with Preeclampsia. Placenta,2009,30:342-347.
7. Joan SH, Margaret G Petroff, Ramsey HM,et al. HLA-G and immune tolerancein pregnancy.FASEBJ,2005,19:681-69
8.王炎秋，邢福祺，陈士岭.甾体激素对绒毛外滋养细胞表达HLA-G蛋白的影响。生殖与避孕，2007，27（4）：260-263。
9. Yie SM, Xiao R, Librach CL. Progesterone regulates HLA-G gene expressionthrough a novel progesterone response element. Hum Reprod,2006,21:2538-2544.
10. Sandra V. Ashton, Guy St. J. Whitley, Philip R. Dash.Uterine Spiral ArteryRemodeling Involves Endothelial Apoptosis Induced by ExtravillousTrophoblasts Through Fas/FasL Interactions. Arterioscler. Thromb. Vasc. Biol,2005，25：102-108.
11. Pierre Fons, Sophie Chabot, Judith E.Soluble HLA-G1inhibits angiogenesisthrough an apoptotic pathway and by direct binding to CD160receptor expressedby endothelial cells.Blood,2006,108：2608-2615.
12. James McCormick, Guy St J. Whitley, Philippe Le Bouteiller and Judith E.Cartwright. Soluble HLA-G regulates motility and invasion of thetrophoblast-derived cell line SGHPL-4. Human Reproduction,2009,24(6):1339-1345.
13.王晓红，孙丽洲。人类白细胞相关抗原G在正常妊娠者及子痫前期患者胎盘组织中的表达研究。海军医学杂志，2009,30（4）：289-292。
14. A.Aris, S.Benali, A, Ouellet, et al. Potential Biomarkers of Preeclampsia: InverseCorrelation between Hydrogen Peroxide and Nitric Oxide Early in MaternalCirculation and at Term in Placenta of Women with Preeclampsia. Placenta,2009（30）:342-347.
15. Yie SM, Li LH, Li YM, et al. HLA-G protein concentrations in maternal serumand placental tissue are decreased in preeclampsia. Am J Obstet Gynecol,2004,191:525-529.
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17. Nagamatsu T, Fujii T,Yamashita T,et al. Hypoxia does not reduce HLA-Gexpression on extravillous cytotrophoblasts. J Reprod Immunol,2004,63:85-9.
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19. Ga l Mouillot, Céline Marcou, Inès Zidi, Christine Guillard.Hypoxia ModulatesHLA-G Gene Expression in Tumor Cells.Human Immunology,2007,68:277–285.
20. Laura Menendez, L DeEtte Walker, Lilya Matyunina, et al. Epigenetic changeswithin the promoter region of the HLA-G genein ovarian tumors. MlolecularCancer,2008, doi:10.1186/1476-4598-7-43.
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1.乐杰主编.妇产科学,第7版.北京:人民卫生出版社,2008,92-100.
2.杨孜,李蓉,石凌蝣,等。早发型重度先兆子痛的临床界定及保守治疗探讨。中华妇产科杂志,2005,40(5):302-305。
3. Branch DW, Andros R, Digre KB, et al. The association of antiphos-pholipidantibodies with severe pre-eclampsia. Obstet Gynecol,1989,73:541-545.
4. Hung TH, SkepperJN, Burton GJ. In vitro ischemia-reperfusion injury in termhuman placenta as a model for oxidative stress in pathological pregnancies. Am JPathol,2001(159):1031-1043.
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6.周雪,孙丽洲,殷茵。子痫前期孕产妇胎盘组织中过氧化氢对人类白细胞相关抗原G表达的影响。中华妇产科杂志,2010,45(5):353-357。
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11. Solier C, Aguerre-Girr M, Lenfant F, Campan A, Berrebi A, RebmannV,Grosse-Wilde H, Le Bouteiller P. Secretion of pro-apoptotic intron4-retainingsoluble HLA-G1by human villous trophoblast. Eur Jimmunol,2002,32:3576–
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2544.
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14. Steinborn A, Varkonyi T scharf A.Early detection of decreased soluble HLA-Glevels in the maternal circulation predicts the occurrence of preeclampsia andintrauterine growth retardation during further course of pregnancy [J].Am JReprod Immunol,2007,57(4):277-286.
15. Eric Jauniaux, Lucilla Poston, and Graham J. Burton. Placental-related diseasesof pregnancy: involvement of oxidative stress and implications in humanevolution. Hum Reprod Update,2006,12(6):747–755.
16. Lockwood cJ, Toti P, Areuri F, et a1.Thrombin regulates soluble fms-liketyrosine kinase-1(sFlt-1) expression in first trimester decidua: implications forpreelampsia [J]. Int J Fertil Womens Med,2007,52(2-3):59-67.
1. Shido F, Ito T, Nomura S, Yamamoto E, Sumigama S, Ino K, et al. Endoplasmicreticulum aminopeptidase-1mediates leukemia inhibitory factor-induced cellsurface human leukocyte antigen-G expression in JEG-3choriocarcinoma cells.Endocrinology,2006,147:1780-8.
2. Catherine Menier, Berta Saez, Vaclav Horejsi, Silvia Martinozzi, IreneKrawice-Radanne, et al. Characterization of Monoclonal Antibodies RecognizingHLA-G or HLA-E: New Tools to Analyze the Expression of Nonclassical HLAClass I Molecules. Human Immunology,2003,64:315–326.
3. Urosevic M，Kurrer MO，Kamarashev J，et al. Human leukocyte antigen Gup-regulation in lung cancer associates with high-grade histology， humanleukocyte antigen class I loss and interleukin-10production. Am J Pathol,2001，159：817-824.
4. Ishitani A, Sageshima N, Lee N, Dorofeeva N, Hatake K, Marquardt H, et al.Protein expression and peptide binding suggest unique and interact-ing functionalroles for HLA-E, F and G in maternal–placental immune recognition. J Immunol,2003,171:1376–8.
5. Kharfi A, Gigue`re Y, De Grandpre′P, Moutquin JM, Forest JC. Humanchorionic gonadotropin (hCG) may be a marker of systemic oxidative stress innormo-tensive and preeclamptic term pregnancies. Clin Biochem,2005,38(8):717–21.
6.孙丽洲，杨娜娜．重度子痫前期患者胎盘滋养细胞凋亡现象的研究．南京医科大学学报：自然科学版，2007，27：1436-1439。
7. Symonds, H., Krall, L., Remington, L., Saenz-Robles, M., Lowe, S., Jacks, T.&Van Dyke, T. p53-dependent apoptosis suppresses tumor growth and progressionin vivo. Cell,1994,78:703-711.
8. Lowe, S. W., Bodis, S., McClatchey, A., Remington, L., Ruley, H. E., Fisher, D.E., Housman, D.E.&Jacks, T. p53status and the efficacy of cancer therapy invivo. Science,1994,266:807-810.
9. Ross, R. The pathogenesis of atherosclerosis: a perspective for the1990s. Nature,1993,362:801-809.
10. Cindrova-Davies T. Gabor than award lecture2008preeclampsia from placentaloxidative stress to maternal endothelial dysfunction. Placenta,2009,30:55-65.
11. T M Johnson, Z X Yu, V J Ferrans, R A Lowenstein, and T Finkel. Reactiveoxygen species are downstream mediators of p53-dependent apoptosis. Proc. Natl.Acad. Sci.1996,93:11848-11852.
12. Eric Jauniaux, Lucilla Poston, Graham J.Burton.Placental-related diseases ofpregnancy: involvement of oxidative stress and implications in human evolution.Human Reproduction Update,2006,12:747–755.
13. Sudjit Luanpitpong, Siera Jo Talbott, Yon Rojanasakul, Ubonthip Nimmannit‖,Varisa Pongrakhananon, Liying Wang and Pithi Chanvorachote. Regulation ofLung Cancer Cell Migration and Invasion by Reactive Oxygen Species andCaveolin-1. Biol Chem.,2010,285(50):38832-40.
14. Huang X, Huang H, Dong M, Yao Q, Wang H. Serum and placental interleukin-18are elevated in preeclampsia. J Reprod Immunol,2005,65:77–87.
1. Boyd JD, Hamilton WJ, Boyd CA. The surface of the syncytium of the humanchorionic villus. J Anat,1968,102(Pt3):553-63.
2. Kaufmann P and Burton GJ. Anatomy and genesis of the placenta. ThePhysiology of Reproduction,1994,2:441–484.
3. Jauniaux E, Gulbis B,Burton GJ. The human first trimester gestational sac limitsrather than facilities oxygen transfer to the foetus: a review. Placenta-Trophoblast,2003,24:86–93.
4. Jauniaux E and Gulbis B. Fluid compartments of the embryonic environment.Human Reprod Update,2000,6:268–278.
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