摘要
目的:妊娠期高血压疾病(hypertensive disorders complicating pregnancy)是妊娠期特有的疾病,是导致孕产妇和围生儿病率及死亡率增加的常见原因之一。子痫前期(preeclampsia,PE)是妊娠期高血压疾病分类中非常重要的一种,尤其是重度子痫前期(severe preeclampsia, sPE )对母儿危害严重,可以导致多器官功能损害。其病因和发病机制至今尚未完全阐明。免疫适应不良学说(immune maladaptation hypothesis)和血管内皮损伤学说是国际上较为公认的两个学说。本研究包括:1)从免疫调控的角度探讨辅助性T细胞(Th)亚群Th1型细胞因子白介素-2(IL-2)、干扰素-γ(IFN-γ)和Th2型细胞因子白介素-10(IL-10)在重度子痫前期发病中的意义;2)探讨对胎盘滋养细胞浸润有调节能力和免疫抑制中起重要作用的细胞因子转化生长因子-β1(TGF-β1)在sPE发病中所起的作用,并且应用变性高效液相色谱仪(DHPLC)和基因测序研究TGF-β1第一号外显子+869位点T/C和+915位点G/C的基因多态性与TGF-β1的产量和sPE发病的关系。3)从内皮细胞损伤的角度探讨血管紧张素Ⅱ(AngⅡ)和血管内皮收缩因子内皮素(ET)在sPE发病中的作用,并研究它们与免疫细胞因子的相关性。4)研究汉族和少数民族子痫前期发病的不同临床特点和妊娠转归。方法:1)第一部分按照重度子痫前期的纳入标准选取在新疆医科大学第一附属医院产科入院的44例患者作为病例组,同时随机选取同期入院的35例血压正常的妊娠产妇作为对照组,采用双抗体夹心酶联免疫吸附测定法(ELISA法,Enzyme linked immunosorbent assay)测定血浆中IL-2、IFN-γ、IL-10的浓度。同时计算Th1/Th(2IL-2/IL-10和IFN-γ/IL-10)比值。2)第二部分取第一部分的44例重度子痫前期患者作为病例组,同时随机选取同期入院的61例血压正常的妊娠产妇作为对照组,采用变性高效液相色谱(DHPLC)技术和基因测序技术分析TGF-β1第一号外显子+869位点T/C(密码子10)和+915位点G/C(密码子25)的基因多态性,同时采用ELISA法测定44例sPE患者和61例对照组中35例正常妊娠妇女的血浆中TGF-β1水平,病例组及对照组与第一部分为同一群体。3)第三部分与第一部分为同一群体,采用放射免疫法测定血浆中内皮素(ET)和血管紧张素Ⅱ(AngⅡ)的水平,分析ET和AngⅡ与IL-2、IFN-γ、IL-10、TGF-β1、IL-2/IL-10比值、IFN-γ/IL-10比值等各细胞因子之间的相关性。4)第四部分通过对我院2003-2007年间收治的295例子痫前期患者进行回顾性分析,按照民族不同将患者分为汉族和少数民族,再按照子痫前期患者发病时间不同分为早发型和晚发型,共分为汉族早发型、汉族晚发型、少数民族早发型、少数民族晚发型四组,分析汉族和少数民族子痫前期患者的发病率,比较四组患者严重并发症的发生情况、胎(婴)儿死亡率比较、临床检测指标比较,分析子痫前期患者各指标与围产结局的相关性。结果:1)与正常妊娠妇女比较,重度子痫前期患者的血浆IL-2水平显著增高(28.38±5.07 VS 35.26±5.97,t=5.43,P<0.001),而血浆IL-10水平显著降低(109.87±34.66 VS 81.15±27.02,t=4.14,P<0.001),血浆IFN-γ水平没有显著差异(42.13±6.36 VS 42.35±4.83,t= 0.175,P>0.05);sPE患者血浆中IL-2/IL-10比值和血浆IFN-γ/IL-10比值均显著高于血压正常的妊娠妇女(分别为0.474±0.149 VS 0.299±0.115,t=5.703,P<0.001和0.530±0.178 VS 0.428±0.142, t=2.77,P<0.01)。2)sPE患者血浆中的TGF-β1的水平是597.01±99.95 pg/ml,而正常对照组孕妇血浆中TGF-β1的水平是543.07±60.92pg/ml,两组相比,差异有统计学意义(t=2.95,P<0.01)。sPE患者TGF-β1第一号外显子+869位点的基因型TT型、TC型、CC型的基因型频率分别为29.5%、56.8%、13.7%,对照组妇女的相应位点的基因型频率分别为37.7%、57.4%、4.9%,两组TT型与TC+CC型基因型频率进行比较,结果显示差异没有统计学意义( x 2=0.755, P =0.385, P>0.05),sPE孕妇+869位点T等位基因频率为42%,C等位基因频率为58%;对照组孕妇T等位基因频率为33.6%,C等位基因频率为66.4%,对两组等位基因频率进行比较,结果显示差异没有统计学意义( x 2=1.559,P=0.212,P>0.05)。sPE患者TGF-β1第一号外显子+915位点的基因型GG型、GC型、CC型的基因型频率分别为77.3%、13.6%、9.1%,对照组妇女的相应位点的基因型频率分别为88.5%、6.6%、4.9%,两组GG型与GC型+CC型基因型频率进行比较,结果显示差异没有统计学意义( x 2=2.385, P =0.123,P>0.05)。sPE孕妇+915位点G等位基因频率为84.1%,C为15.9%;对照组孕妇等位基因频率G为91.8%,C为8.2%,对两组等位基因频率进行比较,结果显示差异没有统计学意义( x 2=3.004,P=0.083,P>0.05)。sPE组和对照组孕妇TGF-β1+869位点TC+CC型与TT型之间血浆TGF-β1水平比较差异均没有统计学意义(t=0.621,P=0.538, P>0.05和t=-1.883,P=0.069, P>0.05); sPE组和对照组孕妇TGF-β1 +915位点GC+CC型与GG型之间血浆TGF-β1水平比较差异没有统计学意义(t=-0.617,P=0.541, P>0.05和t=-0.607,P=0.548, P>0.05)。3)sPE患者的血浆ET水平比正常妊娠妇女显著增高(98.24±45.04 pg/ml VS 68.90±14.36 pg/ml,t'=4.069,P<0.01);sPE患者的血浆AngⅡ水平与正常妊娠妇女相比差异没有统计学意义(54.69±23.69 pg/ml VS 59.34±13.84 pg/ml,t'=1.089,P>0.05)。相关性分析显示重度子痫前期组的血浆ET水平与血浆中的细胞因子IL-2水平、IL-2/IL-10比值、IFN-γ/IL-10比值的相关性有显著的统计学意义,Pearson相关系数分别为0.494、0.465、0.444。重度子痫前期组的血浆AngⅡ水平与血浆中的细胞因子IL-2水平相关性有显著的统计学意义(P<0.01),Pearson相关系数为0.499。重度子痫前期组的血浆IL-10水平与血浆中的细胞因子IFN-γ水平相关性有统计学意义(P<0.01),Pearson相关系数r为0.425。4)汉族和少数民族子痫前期的发病率相比较,差异有统计学意义(2.81% VS 3.66%, x 2=3.98,P<0.05 ),汉族和少数民族早发型子痫前期的发病率相比较,差异有统计学意义(0.92% VS 2.01%,x 2=16.50,P<0.01),少数民族子痫前期发病率尤其是早发型显著高于汉族。汉族早发型组与少数民族早发型组的严重并发症的发生率没有明显差异(90.4% VS 90%,校正x 2=0.07,P>0.05),但少数民族晚发型型组的严重并发症的发生率显著高于汉族晚发型组的严重并发症的发生率(分别为30.3% VS 14.09%, x 2=5.02,P<0.05);汉族和少数民族早发型组的胎(婴)儿死亡率均显著高于晚发型组(14.63%和22.5% VS 5.77%和3.03%, x 2=5.25,P<0.05和校正x 2=4.27,P<0.05)。汉族和少数民族子痫前期患者的临床检测指标相比较,少数民族患者的白细胞计数比汉族患者显著增高(12.74±5.03 VS 9.83±3.05,P<0.001)。少数民族的血红蛋白值显著低于汉族组(109.52±20.94 VS 116.46±19.03,P<0.01)。少数民族组的血浆总蛋白、白蛋白显著低于汉族组(分别为55.43±9.65 VS 49.70±7.23,P<0.001;25.88±7.21 VS 20.94±5.75,P<0.001)。两组的尿素氮和肌酐相比较,差异有统计学意义(5.84±3.50 VS 3.98±1.44,P<0.001;86.48±59.46 VS 64.24±17.48,P<0.01)。用Logistic法对数据进行统计分析,发现分娩孕周、舒张压水平、血浆白蛋白水平、胎(婴)儿出生体重这四项指标具有统计学意义,与围产儿的结局有相关性。结论:1)重度子痫前期的发生与Th1/Th2免疫失衡有关,免疫应答向Th1型偏移,Th1型细胞因子IL-2水平增高和Th2型细胞因子IL-10水平的降低与重度子痫前期的发病机理相关,血浆IL-2/IL-10比值和IFN-γ/IL-10比值的显著增高提示免疫应答激活和免疫耐受不足共同参与了重度子痫前期的发生和发展。2)血浆中TGF-β1水平的增高可能与重度子痫前期的病理生理学变化有关,TGF-β1的第一号外显子+869位点T/C和+915位点G/C的基因多态性与重度子痫前期的发生没有相关性,相应的等位基因不是重度子痫前期的易感基因。这两个位点与TGF-β1的产量也未见明显的相关性。提示在子痫前期的发生中TGF-β1的变化可能与其他基因位点的多态性有关,+869位点和+915位点的基因多态性可能和重度子痫前期的发生无关。3)血浆中血管内皮收缩因子ET水平增高与重度子痫前期的发生有关,与血浆中细胞因子IL-2水平、IL-2/IL-10比值、IFN-γ/IL-10比值有相关性,而且呈正相关;尽管血浆中AngⅡ水平在重度子痫前期患者中没有显著变化,但是其与IL-2水平有相关性,且呈正相关,提示其在重度子痫前期的发病中可能通过细胞因子网络的调节发挥作用。4)少数民族患者子痫前期的发病率尤其是危害严重的早发型子痫前期的发病率显著高于汉族,提示子痫前期的发病有民族差异性,少数民族子痫前期患者可能是很重要的疾病资源库,值得从基因学角度进一步探讨。少数民族子痫前期患者的白细胞计数显著增高、严重的低蛋白血症和贫血可能是临床出现并发症和不良妊娠结局的主要原因。
Objective: Hypertensive disorders complicating pregnancy is a pregnancy-specific syndrome and is one of the leading cause of maternal and fetal mobidity and mortality. Preeclampsia is the most important type of hypertensive disorders complicating pregnancy range from mild to severe. Severe Preeclampsia (sPE) detriment to maternal and fetal the most and may lead to multiple organ function damaged. Although the etiology and pathogensis of preeclampsia are still not unravel, immune maladaptation hypothesis and vascular endothelium cells lesion hypothesis are two theories accepted by most of researchers. Therefore, the present study shed light on several issues as fellows: 1)To investigate the role of T-helper cell subtype including cytokines interleukin-2 (IL-2) and interferon-γ(IFN-γ) of T-helper-type1 (Th1) and cytokine interleukin-10 (IL-10) of T-helper-type2 (Th2) on the pathogensis of sPE based on the theory of immune regulation; 2)To study the contribution of cytokine transforming growth factor-β1 (TGF-β1) which is regulator of placenta trophoblast cell invasion and immune repression on the development of sPE. To analyze the correlation of polymorphisms of TGF-β1 exon 1 +869T/C (Leu10Pro) and +915G/C (Arg25Pro) genotype with severe preeclampsia and production of TGF-β1 by Denaturing High Performance Liquid Chromatography (DHPLC) and direct sequencing. 3)To investigate the role of angiotensinⅡ(AngⅡ) and endothelin (ET) on the pathogensis of sPE from the point of endothelium lesions and to study the correlation of them with immune cytokines detected in Part 1 and Part 2. 4)To explore the different clincal onset patterns and preinatal outcomes in preeclampsia (PE) of Han nationality and national minorities. Methods: 1) Firstly, select 44 cases of sPE hospitalized in the first affiliated hospital in Xinjiang Medical University between April 2006 and September 2007 according to inclusion and exclusion criteria. 35 healthy pregnant women served as controls by random selection. Plasma cytokine levels including IL-2, IFN-γ, IL-10 were assessed by Enzyme linked immunosorbent assay (ELISA) and calculated Th1/Th2(IL-2/IL-10 and IFN-γ/IL-10)ratios. 2) Secondly, same group as part 1 were measured of plasma TGF-β1 levels by ELASA and polymorphisms of TGF-β1 gene exon 1 +869T/C(Leu10Pro, codon 10)and +915G/C(Arg25Pro, codon25)were examined by denaturing high-performance liquid chromatography (DHPLC) and direct sequencing including 44 cases of sPE and 61 cases of control group. 3) Plasma levels of endothelin (ET) and angiotensinⅡ(AngⅡ) were detected by radioimmunoassay on the same group as the part 1, analysed the correlation of plasma ET and AngⅡlevels with plasma cytokine levels of IL-2、IFN-γ、IL-10、TGF-β1、IL-2/IL-10 ratio and IFN-γ/IL-10 ratio. 4) A retrospective observational study was conducted in 295 cases of PE in our hospital on 2003-2007. They were divided into two groups according to the Han nationality (HN) and national minorities (NM). Then according to the onset of gestational age of PE, early onset of PE (onset≤34 weeks) and late onset of PE (onset>34 weeks), they were subdivided into 4 subgroups: NM early onset (40) and late onset (33) of PE, HN early onset (73) and late onset (149) of PE. Clinical characteristic in each subgroup were evaluated. Analyse the mobidity of PE in Han nationality and national minorities. Compare the incidence of serious maternal complications, perinatal mortality rate and clinical index and analyse the correlation of clinical index with perinatal outcome. Results: 1) Plasma levels of IL-2 were much higher in sPE group than that in control group (35.26±5.97pg/ml VS 28.38±5.07pg/ml, t=5.43,P<0.001); Plasma levels of IL-10 were lower in PE group than that in control group (81.15±27.02pg/ml VS 109.87±34.66pg/ml, t=4.14, P<0.001); There were no difference of plasma levels of IFN-γbetween two groups (42.35±4.83pg/ml VS 42.13±6.36pg/ml, t =0.175, P>0.05); IL-2/IL-10 ratio and IFN-γ/IL-10 ratio of plasma in sPE patients were much higher than those in control group (0.474±0.149 VS 0.299±0.115, t=5.703, P < 0.001 and 0.530±0.178 VS 0.428±0.142, t=2.77, P<0.01, respectively). 2) Plasma levels of TGF-β1 were much higher in sPE group than control group (597.01±99.95pg/ml VS 543.07±60.92pg/ml, t=2.95, P<0.01); The genotype distribution frequencies of TGF-β1 gene exon 1 +869T/C (Leu10Pro, codon 10) TT, TC and CC were 29.5%、56.8%、13.7% in sPE group, respectively, while in accordance with those in control group were 37.7%、57.4%、4.9% respectively. There were no difference concerning about genotype frequencies of TT and TC+CC in two groups ( x 2=0.755, P=0.385, P>0.05); The distributions of alleles T and C of +869T/C between sPE group and control group were similar(42% VS 33.6% and 58% VS 66.4%). The genotype distribution frequencies of TGF-β1 gene exon 1 +915G/C (Leu10Pro, codon 10) GG, GC and CC were 77.3%、13.6%、9.1% in sPE group, respectively, while in accordance with those in control group were 88.5%、6.6%、4.9% respectively. There were no difference concerning about genotype frequencies of GG and GC+CC in two groups ( x 2=2.385, P=0.123, P>0.05); The distributions of alleles G and C of +915T/C between sPE group and control group were similar (84.1% VS 91.8% and 15.9% VS 8.2%, x 2=3.004, P=0.083,P>0.05). The plasma levels of TGF-β1 between TC+CC and TT of TGF-β1 +869 locus were similar and the same result appeared with the +915 locus between GC+CC and GG. 3) Plasma levels of ET were much higher in the sPE group than that in control group (98.24±45.04 pg/ml VS 68.90±14.36 pg/ml, t'=4.069,P<0.01) ; whilst plasma levels of AngⅡwere no difference in two groups (54.69±23.69 pg/ml VS 59.34±13.84 pg/ml,t'=1.089, P>0.05). Plasma ET levels in sPE group had correlation with plasma IL-2 levels, IL-2/IL-10 ratio and IFN-γ/IL-10 ratio and Pearson correlation coefficient were 0.494、0.465、0.444. Plasma AngⅡlevels in sPE group had correlation with plasma IL-2 levels which Pearson correlation coefficient were 0.499 and Plasma IL-10 levels in sPE group had correlation with plasma IFN-γlevels which Pearson correlation coefficient were 0.425. 4) The PE incidence of NM was higher than that of HN (3.66% VS 2.81%, x 2=3.98,P<0.05). Especially the PE incidence of NM early onset was much higher than that of HN (2.01% VS 0.92%, x 2=16.50, P<0.01). The incidence of serious maternal complications was much higher in NM late onset subgroup than that in HN late onset subgroup (30.3% VS 14.09%, x 2=5.02, P<0.01), while the incidence of serious maternal complications was not significantly different between NM and HN early onset subgroups (90% vs 90.4% , correction x 2=0.07, P>0.05). Whether in early onset group or late onset group, the perinatal mortality rate were not significantly different between NM and HN (22.5% vs 14.6% and 3.03% vs 5.77% respectively, P>0.05 ) .If compared the perinatal mortality rate between early onset group and late onset group in NM and HN separately, early onset groups were all higher than late onset groups(22.5 vs 3.03% and 14.6% vs 5.77% respectively, P<0.05). The white blood cell count of PE patients in NM groups were much higher than that in HN groups(12.74±5.03 vs 9.83±3.05, P<0.001),in the mean while, Hemoglobin levels, serum total protein and albumin in NM groups were much lower than those in HN groups(109.52±20.94 vs 116.46±19.03, 49.70±7.23 vs 55.43±9.65, 20.94±5.75 vs 25.88±7.21 respectively, P<0.001). Perinatal outcome were associated with gestational age at birth, Neonatal weight, diastolic pressure, serum albumin levels and erythrocyte count. Conclusion: 1) Immune imbalance of Th1/Th2 might be the crucial component of the development of sPE, the immune system in sPE is changed with a shift towards Th1-type immunity. Increased Th1-type cytokine IL-2 and decreased Th2-type cytokine IL-10 in plasma might involove in the pathogensis of sPE. Both IL-2/IL-10 ratio and IFN-γ/IL-10 ratio increased significantly in the sPE patients suggested that overly immune activation and immune intolerance participate in the gensis and development of sPE. 2) Increased TGF-β1 plasma level in sPE patients manifest its role on the pathophysiological processes of sPE. The development of sPE has no correlation with polymorphisms of gene exon 1 +869T/C and +915G/C. The distribution of corresponding allele T and C of +869T/C or allele G and C of +915 G/C were not susceptible gene of sPE and both were not related to the production of TGF-β1. 3) Markedly increased endothelium derived contracting factor ET in plasma and positive correlate with plasma IL-2 level, IL-2/IL-10 ratio and IFN-γ/IL-10 ratio suggested that ET played important role in the development of sPE and can be considered to be the marker of endothelium lesion. Plasma AngⅡlevel appeared of positive correlate with plasma IL-2 level whereas plasma AngⅡlevel has no difference between sPE and normotensive pregancy women suggested that AngⅡmight involve in the development of sPE by regulation of cytokine network. 4) National minorities may be susceptible to PE, especially have a higher incidence to early onset PE which jeopardize perinatal health. It can be a clue to search for genetic factor of PE. Hypoalbuminemia, anemia and inflammatory over-reactive may be contributor factor to the severity and early onset of PE in NM women and might be the main reason of the high incidence of serious maternal complications and unfavorable perinatal outcome.
引文
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