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ORIGINAL RESEARCH |
za Madazl, MDn, MDFrom the Department of Obstetrics and Gynecology, Cerrahpasa Medical Faculty, University of Istanbul, Istanbul, Turkey.
Address reprint requests to: Rza Madazl, University of Istanbul, Department of Obstetrics and Gynecology, 7-8 Ksm, L1-D, D:30, Ataköy, 34750 Istanbul, Turkey; E-mail: madazli{at}ixir.com.
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ABSTRACT |
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METHODS: The study population consisted of 33 women with normotensive pregnancy and 35 women with preeclampsia. Peripheral venous blood samples were collected before labor (35.3 ± 1.1 and 34.2 ± 3.4 weeks’ gestation for normotensive and preeclamptic pregnancies, respectively), and placental tissues were obtained after delivery. Maternal plasma and placental homogenate IL-10, TGF-ß 1, and E-cadherin levels were determined by enzyme-linked immunosorbent assay.
RESULTS: The mean plasma and placental levels of IL-10, TGF-ß 1, and E-cadherin were significantly higher in preeclamptic than normotensive patients (P < .001). The plasma and placental levels of IL-10, TGF-ß 1, and E-cadherin significantly increased with the increments in diastolic blood pressure (P < .001).
CONCLUSION: IL-10, TGF-ß 1, and E-cadherin may be involved in the pathologic process of preeclampsia. The pathophysiologic changes associated with preeclampsia may stem in part from the overproduction of these placental mediators.
Preeclampsia, a syndrome unique to humans, remains the major cause of maternal and perinatal morbidity and mortality worldwide.1,2 Preeclampsia is clearly a complex clinical syndrome potentially involving all of the organ systems. Pathogenesis of preeclampsia seems to be based on a pathologic process at the interface of the fetal and maternal circulation. Placental bed biopsy studies have shown that the basic lesion in the uteroplacental bed seen in preeclampsia is a lack of or an incomplete invasion of trophoblasts into the maternal spiral arteries.3,4 The available evidence supports the view that the origin of this placentation defect is multifactorial; immune maladaptation, genetic predisposition, and intrinsic defect in differentiation of trophoblasts may all play a role.5,6 Pathophysiologic features of preeclampsia, such as increased sensitivity to pressors, activation of the coagulation cascade, and increased vascular permeability, suggest that generalized endothelial cell damage and dysfunction are major features, and the disease may be accepted as an endothelial cell disorder.7 In preeclampsia, there may be placental maladaptation and generalized vascular endothelial cell damage and dysfunction.
Cytokines, growth factors, and adhesion molecules have been proposed as important mediators for successful placentation as well as endothelial dysfunction.8–10 Cytokines, growth factors, and adhesion molecules are both produced by vascular endothelial cells and trophoblasts.8 They all have important functions in the paracrine regulation of trophoblast-endometrial interaction.11,12 The pathophysiologic changes associated with preeclampsia may stem in part from the overproduction of these placental mediators. Interleukin-10 (IL-10), transforming growth factor-ß 1 (TGF-ß 1), and epithelial-cadherin (E-cadherin) have a regulatory function on the extravillous cytotrophoblast invasion and maternal immune adaptation.8,9,12 Variations of these mediators may be involved among the pathophysiologic events initiating the preeclampsia syndrome.
In the present study, we investigated the plasma and placental levels of IL-10, TGF-ß1, and E-cadherin in preeclamptic and normotensive pregnant women. These variables were also correlated with diastolic blood pressure.
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MATERIALS AND METHODS |
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Single peripheral venous blood samples were collected into heparinized vacutainer tubes. Gestational age at sampling was similar in both groups (Table 1
). Plasma samples were isolated by 80,000g centrifugation at 4C for 10 minutes. The samples were stored at -70C until the analyses were performed. Placental tissues were obtained after delivery and immediately placed in liquid nitrogen and stored at -70C until the analyses were performed. Placental tissue fragments (2 g) were thawed and homogenized in 8 mL of ice-cold homogenizing buffer (250 mM of sucrose, 20 mM of Tris hydrogen chloride (HCL), 1 mM of ditriothreitol, pH 7.4) with ultraturrax homogenizers at 1500 rotor per minute (rpm) (Bosch, Switzerland). One portion of homogenates was centrifuged at 120,000g at 4C for 20 minutes for the analyses of IL-10 and E-cadherin. Another 2 g of placental tissue was thawed and homogenized in 8 mL 95% (v/v) of ethanol and concentrated HCL. After overnight extraction at 4C, the mixture centrifuged and the pH was adjusted to 5.2 by ammonium hydroxide. The supernatants were used for placental TGF-ß1 analyses. Plasma and placental levels of IL-10, TGF-ß1, and E-cadherin were quantified by an enzyme-linked immunosorbent assay according to the manufacturer’s instructions, respectively (DRG Instruments GmbH, Germany, and Zymed Laboratories, South San Francisco, CA). The minimal detectable levels of IL-10, TGF-ß 1, and E-cadherin were 1 pg/mL, 1.9 pg/mL, and 0.001 µg/mL, respectively. The intra-assay coefficients of variation for IL-10, TGF-ß 1, and E-cadherin were 3.3%, 1%, and 7.7%, respectively, and interassay coefficients of variation were 2.8%, 7.5%, and 4.6%, respectively. No significant cross-reactivity and interference with factors related to IL-10, TGF-ß 1, and E-cadherin has been noted with these assays.
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RESULTS |
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. The preeclamptic and normotensive groups were well matched. There was no significant difference for age, parity, and gestational age at blood sampling between the groups (P > .05). Of the preeclamptic and normotensive women, 68.6% and 70.5% were nulliparous, respectively. By definition, women with preeclampsia had higher diastolic blood pressure and, as expected, delivered infants earlier with a lower mean birth weight.
Maternal plasma IL-10, TGF-ß 1, and E-cadherin levels of preeclamptic and normotensive pregnancies are illustrated in Table 2. The mean plasma levels of IL-10, TGF-ß 1, and E-cadherin were significantly higher in preeclamptic than normotensive patients (P < .001). Placental IL-10, TGF-ß 1, and E-cadherin levels of preeclamptic and normotensive pregnancies are shown in Table 3. Placental IL-10, TGF-ß 1, and E-cadherin levels were higher than maternal plasma levels. The mean placental levels of IL-10, TGF-ß 1, and E-cadherin were also significantly higher in preeclamptic than normotensive pregnancies (P < .001).
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). The relationship between maternal plasma and placental IL-10, TGF-ß 1, and E-cadherin levels with diastolic blood pressure are shown in Figures 1 and 2, respectively. The plasma levels of IL-10, TGF-ß 1, and E-cadherin significantly increased with the increments in diastolic blood pressure (r = 0.80, r = 0.68, and r = 0.75, respectively). The placental levels of IL-10, TGF-ß 1, and E-cadherin were also found to increase significantly with the increments in diastolic blood pressure (r = 0.72, r = 0.61, and r = 0.82, respectively).
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DISCUSSION |
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or IL-2, suggesting a type of cytokine balance. In this study, the plasma and the placental tissue of preeclamptic women had a significantly higher level of TGF-ß 1 than normotensive women. Maternal plasma and placental concentrations of TGF-ß have also shown to be increased in women with preeclampsia by other studies.21–23 Recently, it has been demonstrated that human placental tissue is a source of TGF-ß, and that it expresses high TGF-ß messenger RNA activity.12,24 Also, TGF-ß is shown to be involved in the paracrine regulation of trophoblast-endometrial interaction and trophoblast differentiation.23,25,26 Thus, it can be speculated that members of the TGF-ß superfamily of growth factors may be involved in the pathogenesis of preeclampsia by inhibiting the differentiation of trophoblasts towards an invasive phenotype.
We have also demonstrated that the plasma and placental tissue of preeclamptic women had significantly higher levels of E-cadherin than normotensive women. In human pregnancy, placental cytotrophoblasts that invade the uterus must lose their epithelial phenotype and transform their cell-cell adhesion molecule phenotype dramatically, both to become invasive and to be able to interact with the endothelial cells.27 Thus, differentiating cytotrophoblast stem cells downregulate adhesion receptors highly characteristic of epithelial cells, such as E-cadherin, and upregulate analogous receptors that are expressed on endothelial cells, such as vascular E-cadherin. Also, E-cadherin has a restraining effect on trophoblast invasiness, whereas contrast vascular E-cadherin normally facilitates trophoblast invasion.27 This switch to a vascular adhesion phenotype that accompanies the differentiation of trophoblasts in normal pregnancy is defective in preeclampsia.28 Our data confirm this hypothesis by demonstrating high placental tissue and plasma E-cadherin levels in preeclamptic patients.
We also found a good correlation between plasma and placental tissue levels of IL-10, TGF-ß 1, and E-cadherin with diastolic blood pressure. This indicates a correlation between the severity of the disease process and the levels of these mediators. Preeclampsia is undoubtedly a complex clinical syndrome, and quite a lot of mediators are involved in this process. Preeclampsia and the severity of the disease appear to originate and correlate with the severity of the pathologic processes at the interface of the fetal and maternal circulation.
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Footnotes |
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Received September 25, 2001. Received in revised form February 14, 2002. Accepted March 14, 2002.
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REFERENCES |
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2. Madazl R, Özgön M, Aksu MF, Köse Y. Maternal mortality in Cerrahpasa Medical Faculty Department of Obstetrics and Gynecology and Intensive Care Unit. In: Weinstein D, Chervenak F, eds. The First World Congress on Maternal Mortality. Bologna, Italy: Monduzz Editore, 1997:145–8.
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