RESUMO
Preeclampsia is a pregnancy-specific disorder characterized by hypertension and systemic endothelial dysfunction. Interleukin (IL)-1ß is a possible mediator of maternal endothelial dysfunction in preeclampsia. Serum IL-1ß as well as its natural inhibitor IL-1 receptor antagonist (IL-1Ra) were reported to be increased in women with preeclampsia. In the current study, we addressed the role of the placenta in controlling the circulatory levels of IL-1ß and its natural inhibitor IL-1Ra in preeclampsia, and the possible effect of magnesium sulfate (MgSO(4)) on these levels. Using an ex vivo placental perfusion system, placentas from preeclamptic (n = 9) and normotensive (n = 6) pregnancies were perfused in presence or absence of MgSO(4). Perfusate samples were collected from the maternal and the fetal circulations of the perfusion system, and IL-1ß and IL-1Ra were examined by enzyme-linked immunoassay (ELISA). Preeclamptic placentas secreted higher levels of IL-1ß (P < 0.001), and a tendentious higher levels of IL-1Ra, mainly into the maternal circulation, as compared with normotensive placentas, although no differences in IL-1ß:IL-1Ra ratio were detected. However, there was only tendentious increase in the secretion levels of IL-1ß or IL-1Ra into the fetal circulation of preeclamptic placentas, when compared with normotensive placentas. Administration of MgSO(4) to preeclamptic placentas resulted in an attenuation of the increased secretion of IL-1ß into the maternal circulation (P < 0.001), and in a tendentious reduction in IL-1Ra. However, IL-1ß:IL-1Ra ratio in preeclamptic placentas was not affected by MgSO(4). Interestingly, exposure of normotensive placenta to MgSO(4) resulted only in increased levels of IL-1Ra in the maternal circulation, without affecting IL-1ß levels or IL-1ß:IL-1Ra ratio. These findings suggest that the placenta may contribute to the elevation in serum IL-1ß and IL-1Ra in preeclampsia by increased secretion of these cytokines into the maternal circulation, and that MgSO(4) is able to attenuate this increased secretion of IL-1ß, and possibly IL-1Ra, in preeclampsia.
Assuntos
Proteína Antagonista do Receptor de Interleucina 1/sangue , Interleucina-1beta/sangue , Sulfato de Magnésio/administração & dosagem , Placenta/metabolismo , Pré-Eclâmpsia/sangue , Pré-Eclâmpsia/tratamento farmacológico , Proteínas da Gravidez/sangue , Tocolíticos/administração & dosagem , Adulto , Feminino , Humanos , GravidezRESUMO
Preeclampsia, one of the main complications in pregnancy, affects 5-7% of all pregnancies, and is a leading cause of maternal and perinatal mortality. The placenta plays a pivotal role in the etiology of preeclampsia, and particularly, the trophoblast cells of the placenta. It is now believed that preeclampsia is a two stage disease. In the first stage, a defective implantation and placentation, causes a reduction in uteroplacental perfusion and placental ischemia/hypoxia. Placental ischemia may promote the release of a variety of factors to the maternal circulation. In the second stage, these factors initiate a cascade of cellular and molecular events leading to endothelial and vascular dysfunction. The endothelial dysfunction leads to the clinically recognized symptoms of the syndrome, which include hypertension, proteinuria, thrombocytopenia and impaired liver function. Hypertension is mediated by various endothelial and non-endothelial regulatory factors that are altered in preeclampsia. This review aims to summarize the recent knowledge on the implication of the placenta and various angiogenic factors in the pathogenesis of preeclampsia.
Assuntos
Pré-Eclâmpsia/fisiopatologia , Doenças Vasculares/fisiopatologia , Citocinas/fisiologia , Feminino , Humanos , Óxido Nítrico/fisiologia , Gravidez , Fator A de Crescimento do Endotélio Vascular/fisiologiaRESUMO
This study has compared the functional capacity of term and preterm placentas in terms of production of pro-inflammatory cytokines in a perfusion system reflecting their ability to react to inflammatory agents, such as lipopolysaccharide (LPS), mimicking the situation of chorioamnionitis. We have demonstrated that term placentas secrete higher levels of tumor necrosis factor (TNF)-alpha compared with preterm placentas. Moreover, TNF-alpha secretion was significantly higher after exposure to LPS in the maternal and fetal sides of term placentas. In contrast, in preterm placentas, only the fetal side responded with a significant increase in secretion of TNF-alpha after exposure to LPS. The maternal side of term placentas secreted significantly higher amounts of interleukin (IL)-6 compared with preterm placentas. Exposure to LPS significantly decreased IL-6 secretion from the maternal side in both term and preterm placentas. Moreover, the fetal side of term placentas secreted significantly lower amounts of IL-6 compared with preterm placentas. In summary, this study has indicated that term and preterm placental tissues have a differing responsiveness to LPS stimulation, with term placentas disposed to a higher TNF-alpha:IL-6 ratio. Release of cytokines into fetal circulation is less than into the maternal side. However, TNF-alpha is released into fetal circulation after LPS stimulation and this may be relevant to the etiology of chorioamnionitis.
Assuntos
Interleucina-6/metabolismo , Lipopolissacarídeos/imunologia , Placenta/imunologia , Placentação/imunologia , Fator de Necrose Tumoral alfa/metabolismo , Ensaio de Imunoadsorção Enzimática , Feminino , Idade Gestacional , Humanos , Interleucina-6/imunologia , Gravidez , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/efeitos dos fármacos , Fator de Necrose Tumoral alfa/imunologiaRESUMO
Three different protocols were carried out to evaluate the effect of magnesium sulfate (MgSO4) on the capacity of the normal human placenta to secrete TNF-alpha and IL-6 in presence and absence of angiotensin II (AII). Ten placentas were perfused with MgSO4 (6-7 mg%) or medium in the absence or presence of AII. Perfusate samples from fetal and maternal sites were collected and examined for IL-6 and TNF-alpha by ELISA. The maternal site of placentas exposed to AII showed only basal levels of TNF-alpha. Exposure of the placentas to MgSO4 resulted in significant increase in TNF-alpha and IL-6 in the maternal site (p < 0.05). However, the effect of MgSO4 was significantly attenuated by AII injected in presence of MgSO4. TNF-alpha and IL-6 levels in the maternal site significantly decreased (p < 0.05). The fetal site of the placentas exposed to MgSO4 or AII separately showed only basal levels of TNF-alpha and IL-6. However, TNF-alpha and IL-6 levels were significantly higher after injection of AII in the presence of MgSO4 compared to TNF-alpha levels in the fetal site of placentas exposed to AII alone (p < 0.05) or MgSO4 alone (p < 0.01). MgSO4 induced the ability of the placental maternal site to secrete TNF-alpha and IL-6. In the presence of both MgSO4 and AII, the effect of MgSO4 on the maternal site was significantly reduced. However, in the fetal site, MgSO4 alone had no significant effect on TNF-alpha and IL-6 levels although, in presence of AII and MgSO4, there was a significant increase in TNF-alpha and IL-6 levels. Elevation of TNF-alpha and IL-6 in the fetal compartment, which may affect fetal brain growth and development and placental function should be considered before administration of MgSO4 during pregnancy.
Assuntos
Angiotensina II/farmacologia , Interleucina-6/metabolismo , Sulfato de Magnésio/farmacologia , Placenta/metabolismo , Tocolíticos/farmacologia , Fator de Necrose Tumoral alfa/metabolismo , Sinergismo Farmacológico , Feminino , Humanos , Interleucina-6/imunologia , Sulfato de Magnésio/efeitos adversos , Troca Materno-Fetal/efeitos dos fármacos , Troca Materno-Fetal/imunologia , Placenta/imunologia , Gravidez , Tocolíticos/efeitos adversos , Fator de Necrose Tumoral alfa/imunologiaRESUMO
The aim of the study was to investigate the stimulatory effect of lipopolysaccharide (LPS) on IL-lalpha production in different compartments of term and preterm placental tissues. Homogenates from amnion, chorion, and from fetal (subchorionic placental tissues, maternal decidua, and mid-placental tissue before and after perfusion of isolated placental cotyledons of 5 term placentas and 4 placentas obtained after preterm birth (28-34 W of gestation) were examined. Isolated placental cotyledons were dually perfused LPS (100 ng/kg perfused placental tissue) was perfused into the maternal side during 10 hours. Homogenates of the samples were examined by ELISA for IL-1alpha levels, and paraffin sections of the samples were stained by immunohistochemical staining, to characterize the cellular origin of placental IL-1alpha. Paired t test and ANOVA determined statistical significance. In the homogenates, there was a tendency towards higher IL-lalpha levels in all preterm placental compartments as compared to the term compartments before perfusion. A significant increase was observed only in the chorion compartment (p = 0.035). LPS had significantly increased IL-la levels only in the decidua compartment of term placentas as compared to other placental compartments (p = 0.0004), and had decreased IL-1alpha levels in the mid-placenta (p = 0.034). In preterm placentas, addition of LPS did not affect the expression levels of IL-1alpha in either fetal or maternal compartments as determined by ELISA and immunohistochemical staining. IL-la levels in the chorion compartment of preterm placenta were significantly higher as compared to term placenta. LPS affects placental tissues of term and preterm placentas differently. Also, in the term placentas, LPS affected the different compartments differently. Thus, IL-1alpha may have a key role (as a autocrine/paracrine factor) in the regulation of normal and pathological pregnancy and parturition.
Assuntos
Membranas Extraembrionárias/metabolismo , Interleucina-1/biossíntese , Lipopolissacarídeos/administração & dosagem , Placenta/metabolismo , Comunicação Autócrina , Ensaio de Imunoadsorção Enzimática , Membranas Extraembrionárias/citologia , Feminino , Idade Gestacional , Humanos , Imuno-Histoquímica , Técnicas In Vitro , Comunicação Parácrina , Perfusão , Placenta/citologia , Gravidez , Nascimento Prematuro/metabolismoRESUMO
Our in vitro perfusion study confirms the result of the Boskovic et al., that insulin lispo is not crossing the human placental membranes at low concentrations. In our study maternal steady state concentration reached 48 +/- microU in the maternal artery and 28 +/- 1 microU in the maternal vein, while in the fetal site insulin lispo was not detected. However, the concentration of insulin lispo in placental tissue was 1836 +/- 220 microU.
Assuntos
Insulina/análogos & derivados , Insulina/sangue , Troca Materno-Fetal , Placenta/metabolismo , Feminino , Humanos , Insulina/análise , Insulina Lispro , Placenta/química , GravidezRESUMO
PROBLEMS: To determine if magnesium sulfate (MgSO4) attenuates the vasoconstrictor effect of angiotensin II (Ag II), endothelin-1 (ET-1) and thromboxane mimetic (TX) in the human fetal placental vasculature and if interleukin-1 beta (IL-1beta) is involved in this process. STUDY DESIGN: Isolated placental cotyledons (n = 18) were dually perfused with fetal perfusion pressure used as an index of vascular response. The vasoconstriction effect of bolus injection of various concentrations of Ag II (10(-1)) 10(-6) M) or ET-1 (10-(10)-10(-4) M) or TX (10(-10)) 10(-5) M) was established in the absence or presence of MgSO4 (7 mg% constant infusion during 10 hr). Statistical significance was determined by paired t-test and ANOVA. RESULTS: MgSO4 significantly attenuates the vasoconstrictor effect of Ag II in the fetal placental vasculature in the human placenta (P = 0.02). Moreover, significant attenuation of vasoconstrictor response to ET-1(10(-10))10(-5) M) was observed in the presence of MgSO4 (P = 0.02). However, no attenuation of the vasoconstrictor response to TX was noted in the presence of MgSO4 (P > 0.5). Ag II and TX were shown to induce IL-1beta secretion by placental tissue. This effect was completely reduced by perfusion of MgSO4 (7 mg%; constant infusion). CONCLUSIONS: MgSO4 significantly attenuates the vasoconstrictor effect of Ag II and ET-1 in the fetal-placental vasculature in the human placenta, but not that of TX. Inhibition of local production of IL-1beta could be one of the mechanisms used by MgSO4 to reduce the vasoconstrictory effect of Ag II and TX in human placental cotyledone.
Assuntos
Sulfato de Magnésio/farmacologia , Placenta/irrigação sanguínea , Placenta/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia , Angiotensina II/farmacologia , Endotelina-1/farmacologia , Feminino , Humanos , Interleucina-1/metabolismo , Placenta/metabolismo , Gravidez , Especificidade por Substrato , Tromboxanos/farmacologiaRESUMO
The human placenta is the interface between the mother and fetus in the uterus. Until recently it was generally believed that the uterus provides a protective environment for the fetus. It is now accepted that any chemical substance, including any therapeutic agent, administered to a mother is able to permeate across the placental barrier. Unfortunately, the placental transfer of substances and their distribution in the placenta is not well established. Understanding the structure of placental transporters and their function may serve as the ideal tool for drug development and the cure of mother and fetus during pregnancy.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Hipoglicemiantes/farmacocinética , Troca Materno-Fetal/fisiologia , Placenta/fisiologia , Transporte Biológico/fisiologia , Feminino , Humanos , GravidezRESUMO
OBJECTIVE: To determine the effect of quinidine and verapamil, known antiarrhythmic agents and P-glycoprotein (Pgp) inhibitors, on digoxin transport from the maternal to the fetal compartment in the isolated perfused human placenta. STUDY DESIGN: Isolated placental cotyledons from normal human placentae (n=20) were dually perfused with M199 medium enriched with albumin (0.3%) and glucose (0.1%). The maternal and the fetal circulation flow rates were 12 and 6 ml/min, respectively. Closed circulations were used to evaluate steady state transplacental gradient formation. In six placentae quinindine was added to the maternal circuit; after 45 min of perfusion, digoxin was added to the maternal circulation. The effect of verapamil on digoxin transfer from the maternal to the fetal compartments was explored in five placentae. In six additional placentae the transfer of digoxin was studied in the absence of quinidine. Transplacental passage of digoxin was calculated from repeated fetal and maternal perfusate samples. Digoxin levels were determined in perfusate samples by fluorescence polarization immunoassay. Antipyrine was added to the maternal reservoir of all placentae as reference substance. RESULTS: The transfer of digoxin (alone) and in the presence of quinidine or verapamil was 10.93+/-3.71, 9.00+/-5.2 and 12.94+/-4.86%, respectively. The levels of digoxin in the fetal compartment, 0.62+/-0.20, 0.48+/-0.29 and 0.60+/-0.26 ng/ml, respectively, were not significantly affected by quinidine and verapamil. These Pgp modulators, also did not influence significantly the steady state levels of digoxin in the maternal compartment. CONCLUSION: Neither quinidine nor verapamil affected the transplacental transfer of digoxin in vitro in normal human placentae. In contrast to the other tissues, they do not inhibit Pgp activity in term human placentae.
Assuntos
Subfamília B de Transportador de Cassetes de Ligação de ATP/antagonistas & inibidores , Digoxina/farmacocinética , Troca Materno-Fetal/efeitos dos fármacos , Placenta/metabolismo , Quinidina/farmacologia , Verapamil/farmacologia , Antiarrítmicos/farmacocinética , Antiarrítmicos/farmacologia , Transporte Biológico/efeitos dos fármacos , Interações Medicamentosas , Inibidores Enzimáticos/farmacologia , Feminino , Humanos , Técnicas de Cultura de Órgãos , Placenta/efeitos dos fármacos , GravidezRESUMO
We report a rare case of a cavernous transformation of portal vein (CTPV) thrombosis accompanied by Thalassemia and thrombophilia during pregnancy that was successfully treated by low molecular weight heparin. The clinical presentation, diagnosis and the treatment are discussed.
Assuntos
Veia Porta , Complicações Cardiovasculares na Gravidez , Talassemia/complicações , Trombose Venosa/etiologia , Dor Abdominal , Adulto , Cesárea , Feminino , Idade Gestacional , Heparina de Baixo Peso Molecular/uso terapêutico , Humanos , Recém-Nascido , Fígado/irrigação sanguínea , Masculino , Gravidez , Talassemia/diagnóstico , Tomografia Computadorizada por Raios X , Trombose Venosa/diagnóstico , Trombose Venosa/tratamento farmacológicoRESUMO
OBJECTIVE: The aim of our study is to determine whether oxytocin acts differently on the fetal-placental vascular bed of normal and meconium impregnated placentas. STUDY DESIGN: Isolated placental cotyledons (n=10) were dually perfused with fetal perfusion pressure used as an index of vascular resistance. As perfusion medium we used lactated Ringer salt solution, containing polyvinylpyrolidone (25 g/l), bovine serum albumin (0.1 mg/ml), glucose (1.0 g/l), heparin (20 IU/ml) and gentamycin (48 microg/ml). The pH of the medium was adjusted to 7.4 with bicarbonate. The maternal site was gassed with 95% O(2):5% CO(2) and in the fetal site with 95% N(2):5% CO(2) at 37 degree C. Perfusion rates were 4-6 and 10-12 ml/min in the fetal and maternal circulation, respectively. TNF-alpha and IL-beta1 levels in the fetal-placental perfusate were evaluated using specific commercial ELISA kits. RESULTS: No significant changes in the amount of TNF-alpha release were observed after injection of oxytocin into the fetal circulation (31+3pg/ml; P=0.5). No IL-beta1 activity was observed in the fetal perfusate of normal and meconium impregnated placentas during the experiments. No significant difference was seen in basal perfusion pressure in normal and meconium impregnated placentas, however, a bolus injection of oxytocin (10U/ml) resulted in a significant increase in perfusion pressure in meconium impregnated placentas from basal pressure of s45+5 to 88+4 mm Hg after injection of oxytocin, (P=0.004, ANOVA). CONCLUSION: Vasoconstrictive effect of oxytocin was observed only in meconium impregnated placentas and no vascular effect of oxytocin was documented in normal placentas. The clinical implication of our findings is that one should use oxytocin for stimulation of labor with caution in the presence of meconium stained amniotic fluid.