Alessia Giovannelli

Urocortin increases IL-4 and IL-10 secretion and reverses LPS-induced TNF-alpha release from human trophoblast primary cells.

Problem  As urocortin (Ucn) is a placental peptide belonging to the corticotrophin‐releasing hormone (CRH) family that modulates immune function in other biological models, this study evaluated Ucn effects on cytokines secretion from cultured human trophoblast cells.

ORIGINAL ARTICLE: Urocortin Increases IL-4 and IL-10 Secretion and Reverses LPS-induced TNF-α Release from Human Trophoblast Primary Cells

Problem  As urocortin (Ucn) is a placental peptide belonging to the corticotrophin‐releasing hormone (CRH) family that modulates immune function in other biological models, this study evaluated Ucn effects on cytokines secretion from cultured human trophoblast cells.

High maternal and fetal plasma urocortin levels in pregnancies complicated by hypertension.

Objective We evaluated maternal and fetal plasma levels and placental mRNA expression of urocortin, a placental vasoactive neuropeptide, in singleton pregnancies (n = 70) complicated by hypertensive disorders classified as gestational hypertension (n = 36), pre-eclampsia (n = 19), and pre-eclampsia complicated by intrauterine growth restriction (PE/IUGR, n = 15), and in 70 healthy normotensive singleton pregnancies. Methods Plasma levels were assayed by radioimmunoassay, fetal biometry by ultrasound scans, utero-placental and fetal perfusion by Doppler velocimetry, and placental urocortin mRNA expression by quantitative real time reverse transcriptase-polymerase chain reaction. The main outcome measures were the correlation of urocortin concentrations with patterns of the utero-placental and fetal circulation, and the early prediction of a poor neonatal outcome such as the occurrence of perinatal death and intraventricular hemorrhage. Results Maternal and fetal urocortin levels were significantly (both P < 0.001) higher in gestational hypertension, pre-eclampsia and PE/IUGR women than in controls, and correlated with Doppler velocimetry patterns. Fetal concentrations were significantly (P < 0.0001) higher than and significantly (P < 0.0001) correlated to maternal levels. Placental mRNA expression did not change. Ten out of 140 newborns had a poor neonatal outcome, with an overall prevalence of 7.14% (pretest probability). Using the receiver operator characteristics curve analysis cut-off values, the probability of a poor neonatal outcome was 66.7% when urocortin was used, and was 0% if levels were unaltered. Conclusions Maternal and fetal urocortin levels are increased in hypertensive disorders of pregnancy. Since urocortin has vasoactive properties, the evidence of increased urocortin levels in hypertensive disorders may represent an adaptive fetal response.

Labor (Term and Preterm) Is Associated With Changes in the Placental mRNA Expression of Corticotrophin-Releasing Factor

Because maternal plasma corticotrophin-releasing factor (CRF) levels increase during the last weeks of pregnancy and at parturition, the present study evaluated whether placental mRNA expression of CRF and CRF-binding protein (CRF-BP) are modified in preterm delivery. A group of 30 women with singleton pregnancies were enrolled in the study. A placental tissue specimen was collected from pregnant women (1) at term after cesarean delivery (39.3 ± 0.1 gestational weeks; n = 10), (2) at term after spontaneous vaginal delivery (40.1 ± 0.2 gestational weeks; n = 10), or (3) at preterm delivery (32.4 ± 0.4 gestational weeks; n = 10). Changes of placental mRNA expression were evaluated by real-time quantitative reverse transcriptase polymerase chain reaction analysis. Placental CRF mRNA expression at term (P < .001) and preterm delivery (P < .001) was significantly higher than in cesarean delivery and highest in preterm placentas. With respect to CRF-BP, no significant difference in placental mRNA expression was observed among samples collected after term or preterm delivery and cesarean delivery. The present study showed for the first time that both term and preterm labor are associated with increased expression of placental CRF but not CRF-BP mRNA.

Amniotic fluid urocortin, CRF, oestriol, dehydroepiandrosterone sulfate and cortisol concentrations at mid-trimester: putative relationship with preterm delivery

OBJECTIVE Stress-related peptide and steroid hormones are involved in the pathogenesis of preterm delivery, even though their clinical usefulness as predictive markers of preterm delivery remains unclear. The present study evaluated whether mid-trimester amniotic fluid concentrations of stress-related peptides, that is corticothophin-releasing factor (CRF) and urocortin (Ucn) and feto-placental steroids (oestriol, DHEA-S and cortisol) correlated with preterm delivery. STUDY DESIGN It is a retrospective case-control study. Healthy women (n=130) undergoing amniocentesis at mid-gestation for genetic indications, of whom 15 had a preterm delivery (cases) and 115 delivered at term (controls). CRF, urocortin, cortisol, DHEA-S and oestriol concentrations were measured by specific and sensitive immunoenzymatic assays. RESULTS Amniotic fluid urocortin concentrations in the cases (0.50+/-0.07 ng/ml) (M+/-SD) were significantly lower (P<0.0001) than in the control group (0.90+/-0.26 ng/ml), while CRF concentrations did not differ between the cases (1.52+/-0.39 ng/ml) and control group (1.64+/-0.68 ng/ml). Amniotic fluid cortisol (17.71+/-3.72 ng/ml vs. 17.32+/-3.17 ng/ml), DHEA-S (0.16+/-0.06 ng/ml vs. 0.17+/-0.09 ng/ml) and oestriol (4.68+/-1.95 ng/ml vs. 4.79+/-1.84 ng/ml) concentrations were similar in the two groups. CONCLUSIONS The low amniotic fluid concentrations of urocortin at mid-trimester may be a signal of predisposition to preterm delivery, while the unchanged CRF and steroid hormones concentrations in women delivering preterm suggest that this mechanisms are not yet activated at mid-trimester.

Corticotrophin-releasing Factor and Urocortin Inhibit System A Activity in Term Human Placental Villous Explants

Plasma corticotrophin-releasing factor (CRF) and urocortin are elevated in preterm labour and/or fetal growth restriction (FGR). FGR is associated with reduced placental system A amino acid transporter activity and in vitro data suggest altered endocrine status could be responsible. Here we test the hypothesis that CRF and urocortin inhibit placental system A activity. Chronic (48h) exposure of term placental villous explants to these hormones (10(-7)M) significantly reduced system A activity (Na(+)-dependent (14)C-methylaminoisobutyric acid uptake), whereas 1h exposure had no effect. We propose elevated CRF and urocortin contribute to FGR through negative regulation of placental system A activity.

Maternal plasma corticotropin-releasing factor (CRF) and CRF-binding protein (CRF-BP) levels in post-term pregnancy: effect of prostaglandin administration.

OBJECTIVE Placental corticotropin-releasing factor (CRF) affects myometrial contractility and the secretion of several uterotonins such as prostaglandins (PGs); however, the activity of CRF is counteracted by CRF-binding protein (CRF-BP). At term and pre-term labor, CRF levels in maternal plasma are highest whereas those of CRF-BP are falling, and the cause of this fall is unknown. Thus, in this study, we investigated the effect of PG administration for labor induction on maternal plasma CRF and CRF-BP concentrations. DESIGN Maternal plasma CRF and CRF-BP levels were assayed before and after (2 h later) induction of labor by intracervical administration of prostaglandin E(2) (PGE(2)), and at delivery in a group of healthy post-term pregnancies (n=18). Controls were women at term out of labor (n=22), who subsequently progressed to deliver a healthy singleton baby. METHODS CRF was measured by two-site immunoradiometric assay, and CRF-BP was assayed by radioimmunoassay. RESULTS Maternal plasma CRF levels were significantly (P<0.0001) lower and CRF-BP significantly (P<0.0005) higher in post-term than in term pregnancies. With respect to induction of labor, 2 mg PGE(2) were sufficient to increase maternal plasma CRF levels at delivery (P<0.005). While 0.5 mg PGE(2) significantly decreased maternal plasma CRF-BP levels at delivery (P<0.001), 2.0 mg PGE(2) significantly reduced CRF-BP concentrations both after 2 h (P<0.05) and at delivery (P<0.0001). CONCLUSIONS In the light of the well-known stimulation of prostaglandin release by CRF, these data suggest a positive feedback effect of PGE(2) on maternal CRF release during induced labor.

ORIGINAL ARTICLE: Urocortin Increases IL-4 and IL-10 Secretion and Reverses LPS-induced TNF-α Release from Human Trophoblast Primary Cells: UROCORTIN AND MODULATION OF PLACENTAL CYTOKINE SECRETION

Problem  As urocortin (Ucn) is a placental peptide belonging to the corticotrophin‐releasing hormone (CRH) family that modulates immune function in other biological models, this study evaluated Ucn effects on cytokines secretion from cultured human trophoblast cells.

379 Maternal Plasma Urocortin I Levels in Preeclampsia and Fetal Growth Restriction Predict Neonatal Intraventricular Haemorrhage

Urocortin I levels were measured in maternal plasma collected from women with gestational hypertension (GH; n=70), preeclampsia (PE; n=19), PE with superimposed fetal growth restriction (PE+FGR; n=15), and controls (n=70), and also in umbilical cord plasma collected at delivery from a subset of patients (Controls: n=11; GH: n=10; PE: n= 11; PE+FGR: n=9). The correlation of maternal plasma urocortin measurement with the occurrence of perinatal intraventricular hemorrhage (IVH) was also evaluated. In all cases ultrasound scanning, Doppler velocimetry patterns of the uterine artery resistance index (UtA RI) and the umbilical cord artery vessels, and samples were collected before birth. Maternal levels were significantly higher in GH (P<0.05), PE (P<0.001) and PE+FGR (P<0.001) than in controls. PE+FGR had the highest urocortin levels, significantly (P<0.001) higher than PE and GH. In umbilical cord levels were significantly (P<0.0001) higher in GH, PE and PE+FGR than in controls; and significantly (P<0.001) higher in PE+FGR than in GH and PE. Concentrations were significantly (P<0.0001) higher than, and correlated to maternal levels. Eleven out of 140 patients developed IVH, giving an overall prevalence of the disease in our population of 7.14% (pretest probability). By using the cut-offs indicated by the ROC curve analysis, when mean UtA RI was used the probability of developing IVH (positive predictive value) was 28.6% (C.I.95%: 0.6–56.6%), and 0% if it was not altered, respectively. By using urocortin, the probability of IVH was 66.7%, and 0% if levels were unaltered. In conclusion, urocortin I levels are increased in maternal and fetal circulation in presence of hypertensive disorders of pregnancy, and their changes are correlated with neonatal IVH.