| Background: Preeclampsia is a type of gestational hypertension and one of the most important causes of maternal and perinatal deaths. Despite the greatly improved efficacy in recent years, its etiology and the mechanisms underlying its pathogenesis are still elusive, and specific diagnostic modalities and treatment regimens are still unavailable to date. Therefore, preeclampsia still represents one of the important research topics in perinatal medicine.Recent molecular biology and genetic immunology studies suggest that the influence of multiple genetic factors result in changes in more than one site in the same susceptibility gene or (and) changes in different susceptibility genes, which, in combination with the interactions of external environmental factors where different organisms are located, may eventually lead to the development of preeclampsia.The most important pathophysiological change in preeclampsia is the injury of systemic vascular endothelial cells in patients. Current findings suggest that a significantly imbalanced regulation in cytokines is present in patients, thereby leading to vascular endothelial injury. However, these cytokines which play a core regulatory role in pregnancy immunity are predominantly secreted by the T helper cell subsets (T1 and T2).Thl cytokines detrimental to pregnancy and Th2 cytokines that protect pregnancy in normal pregnant women are respectively reduced and increased compared to non-pregnant women, which help embryo implantation and facilitate pregnancy, thus reaching a regulatory adaptation state.IL-10 is an important Th2 cytokine that negatively regulates the Thl-mediatted immune responses,and its level of secretion is affected by genetic factors. Since the polymorphisms of gene promoters affect gene transcription,function and phenotypes,there are currently few studies reporting the correlation between polymorphisms of the IL-10 gene and preeclampsia, and meanwhile, the results published are controversial.Therefore, we firstly conducted a case-control study to investigate the role of polymorphisms of the IL-10 gene (-1082A/G, -819T/C and -592A/C) in the development and progression of early-onset of preeclampsia, thereby providing possible genetic basis for its pathogenesis.Section 2 is the clinical study. Gene polymorphisms in patients lead to different secretion levels of cytokines such as IL-10, which results in inflammatory stimulation-induced injury of vascular endothelial cells, prethrombotic state and thrombosis in all viscera within bodies, blood hypercoagulability, functional injury of organs and finally clinical symptoms. Both domestic and foreign scholars have used low molecular weight heparin and other treatment modalities for blood hypercoagulability-induced pregnancy complications, such as preeclampsia, intrauterine growth restriction, habitual abortion and pregnancy thrombosis, etc., while these findings are still controversial.Diminished invasiveness of placental trophoblasts and restricted spiral small arterial resuscitation contribute to shallow placental implantation, and they are now considered the root cause of preeclampsia onset. During pregnancy, activin A and inhibin A display a significant regulatory effect on the differentiation and infiltration of trophoblasts in the initial stage of pregnancy. Foreign studies have shown that both the level and activity of inhibin A and activin A are significantly increased in the peripheral blood of patients with preeclampsia, while the number of relevant reports in China is still very limited in view of the medical conditions.Based on the previous study, we further explored the subcutaneous injection of low molecular weight heparin in addition to the conventional expectancy therapy for anticoagulation in patients with early-onset severe preeclampsia. The differences in such clinical indicators as termination time of pregnancy, perinatal outcomes, urinary protein,urine output, blood pressure, blood coagulation indexes, uterine artery, umbilical artery blood flow resistance, subjective symptoms, mode of delivery and postpartum hemorrhage were observed, and the changes in the levels of activin A and inhibin A which had significant regulatory effects on the differentiation and infiltration of trophoblast cells were detected. We further gained an insight into the significance of low molecular weight heparin for the treatment of patients with severe early preeclampsia so as to clearly define the specific biological mechanisms underlying it, thereby providing relevant data for the treatment of preeclampsia.This study includes 2 sections, which are summarized as follows.Section 1Study on Association of IL-10 Gene Polymorphism with a Risk of Early-onset PreeclampsiaObjective: To study the relationship between IL-10 gene polymorphisms (-592A/C,-819T/C and -1082A/G) and early-onset preeclampsia.Methods: A case-control study was performed. A total of 177 patients with early-onset preeclampsia were selected and 182 normal pregnant women were used as the control group. 2 ml of peripheral blood was sampled for anticoagulation using EDTA. Genomic DNA of all subjects was extracted using the peripheral blood genome extraction kit(Qiagen, Germany), and their concentration and purity of DNA were found to be qualified. The polymorphisms of the -592A/C (rs1800872) , - 819T/C (rs 1800871) and IL-10-1082A/G (rs 1800896) were detected by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method, and the forward and reverse primers of the IL-10 SNP site were designed as follows:IL-10 -1082A/G F:5'-TGATTGTATCTCGTCCAGATCC-3';-1082A/G R:5'-TCCGGCAAGTGCCTAAGTGA-3';IL-10 -819T/C F:5'-TGATTGTATGTGCTCCAGATCC-3';-819T/C R:5'-TGGGCCAAGTGCCTA AG AGT-3'; IL-10 -592A/C F:5'-GGTCAGCAGTACCTGAGTAGC-3';-592A/C R:5'-GGTAGGACTCTGTGACGTCC-3'. The target bands were amplified using PCR.The DNA products were subjected to 3.5% agarose gel electrophoresis, stained with ethidium bromide (EB) and finally observed on a gel imager.Results: The chi-square test showed that there were no significant changes in gene frequencies of -1082A/G, -819T/C and -592A/C polymorphism of IL-10 between the study group and the control group, and the P values of the Hardy- Weinberg Equilibrium(HWE) were 0.46, 0.17 and 0.18, respectively. Besides, the minor allele frequencies(MAF) were also consistent with the results from the dbSNP database, indicating that the genetic balance was achieved, or the data of this group investigation was credible. The results of the unconditional logistic regression analysis showed that pregnant women carrying the CC genotype of IL-10-819T had a greater risk (1.71, 1.07-3.27) of early-onset preeclampsia than those carrying the TT genotype, while pregnant women carrying 1082A/G and -592A/C genotypes were not significantly associated with the risk.Conclusion: IL-10-819T/C polymorphism may result in an increased risk of preeclampsia in pregnant women in the eastern coastal regions of China.Section ?Study on low molecular weight heparin for the treatment of early-onset severe preeclampsiaObjective: To study the clinical efficacy of low molecular weight heparin for the treatment of patients with severe early-onset preeclampsia and its effects on the levels of serum activin A and inhibin A.Methods: A total of 116 patients with severe early-onset preeclampsia were selected,with 120 normal pregnant women hospitalized at the same period as the controls. 60 patients who were given conventional expectation therapy were classified into the routine treatment group, and 56 patients who were provided routine treatment plus low molecular weight heparin 5000IU through subcutaneous injection were included in the study group.Blood coagulation, blood pressure, urine protein, subjective symptoms, time of gestational extension, delivery mode, amount of postpartum bleeding, liver and renal function indicators, uterine artery and umbilical artery blood flow resistance and neonatal conditions between the 2 groups were compared, and the changes in the levels of activin A and inhibin A in severe early-onset preeclampsia patients after short-term treatment were observed.Results: The blood pressure, urinary protein, the rate of hypoalbuminemia, uterine artery and umbilical artery blood flow resistance and the rate of neonatal asphyxia were higher in the preeclampsia group than in the normal pregnancy group. Patients in the low-molecular-weight heparin treatment group for the early period of severe early-onset preeclampsia had improved blood coagulation, reduced blood pressure, reduced urinary protein, improved overall symptoms, extended gestational age on expectation therapy, no increased postpartum hemorrhage, decreased uterine artery and umbilical artery blood flow resistance and decreased neonatal asphyxia rates as compared with those in the conventional treatment group; in addition, there were no differences in mode of delivery and liver and renal function indicators between the 2 groups. However, the levels of serum inhibin A and activin A were not significantly different in patients with preeclampsia between the 2 groups regardless of their administration of low molecular weight heparin or not.Conclusions: Short-term administration of low molecular weight heparin for severe early-onset preeclampsia patients could improve the clinical therapeutic effects of both mothers and neonates, while did not affect the levels of inhibin A and activin A secretions. |
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