| 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.
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