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ABSTRACT: OBJECTIVE: Cross-talk between inflammation and angiogenesis pathways has been recently reported. The objectives of this study were to: (i) examine whether amniotic fluid (AF) concentrations of soluble endoglin (sEng), a protein with anti-angiogenic properties, change during pregnancy, parturition, or intra-amniotic infection and/or inflammation (IAI); (ii) determine whether an increase in sEng in the AF of patients with preterm labor (PTL) and preterm prelabor rupture of membranes (PROM) is associated with adverse neonatal outcomes; and (iii) investigate potential sources of sEng in AF. STUDY DESIGN: A cross-sectional study was conducted to include patients in the following groups: (i) mid-trimester (n = 20); (ii) PTL with term delivery (n = 95); (iii) PTL leading to preterm delivery with (n = 40) and without IAI (n = 46); (iv) preterm PROM with (n = 37) and without IAI (n = 37); (v) term in labor (n = 48) and not in labor (n = 44). AF concentrations of sEng were determined by enzyme-linked immunosorbent assay. Chorioamniotic membranes, umbilical cord blood, and AF macrophages were examined for the expression of endoglin. RESULTS: (i) Patients with IAI had a higher median AF concentration of sEng than those without IAI (P = 0.02 for PTL and 0.06 for preterm PROM); (ii) AF concentrations of sEng in the 3rd and 4th quartiles were associated with IAI (OR 2.5 and 7.9, respectively); (iii) an AF sEng concentration ≥779.5 pg/mL was associated with bronchopulmonary dysplasia (BPD) (OR 7.9); (iv) endoglin was co-localized with CD14+ macrophages in AF pellets of patients with IAI by immunofluorescence and flow cytometry; and (v) the concentration of sEng in the supernatant was significantly increased after the treatment of macrophages with endotoxin or TNF-α. CONCLUSIONS: Soluble endoglin participates in the host response against IAI. Activated macrophages may be a source of sEng concentrations in the AF of patients with IAI. An increase of sEng in the AF is associated with BPD and adverse neonatal outcomes.
American Journal Of Reproductive Immunology 12/2012; · 2.17 Impact Factor
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ABSTRACT: Glycogen phosphorylase is a key enzyme in glycogenolysis. Released with myocardial ischemia, blood concentration of glycogen phosphorylase isoenzyme BB (GPBB) is a marker of acute coronary syndromes. Pregnancy imposes metabolic stress, and preeclampsia is associated with cardiac complications. However, plasma GPBB concentration during pregnancy is unknown. This study was conducted to determine maternal plasma GPBB concentration in normal pregnancy and in preeclampsia. Plasma samples from 6 groups (n=396) were studied: nonpregnant and pregnant women with normal term delivery, term and preterm preeclampsia, and term and preterm small-for-gestational-age neonates. GPBB concentration was measured with a specific immunoassay. Placental tissues (n=45) obtained from pregnant women with preterm and term preeclampsia, spontaneous preterm delivery, and normal term delivery were analyzed for potential GPBB expression by immunoblotting. Median plasma GPBB concentration was higher in pregnant women than in nonpregnant women (38.7 versus 9.2 ng/mL; P<0.001), which remained significant after adjusting for age, race, and parity. Maternal plasma GPBB concentrations did not change throughout gestation. Cases of preterm (but not term) preeclampsia had higher median plasma GPBB concentrations than gestational age-matched normal pregnancy cases (72.6 versus 26.0 ng/mL; P=0.001). Small-for-gestational-age neonates did not affect plasma GPBB concentration. GPBB was detected in the placenta and was less abundant in preterm preeclampsia than in preterm delivery cases (P<0.01). There is physiological elevation of plasma GPBB concentration during pregnancy; an increase in maternal plasma GPBB is a novel phenotype of preterm preeclampsia. It is strongly suggested that these changes are attributed to GPBB of placental origin.
Hypertension 01/2012; 59(2):274-82. · 6.21 Impact Factor
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Deug-Chan Lee,
Roberto Romero,
Jung-Sun Kim,
Adi L Tarca,
Daniel Montenegro,
Beth L Pineles,
Ernest Kim,
JoonHo Lee,
Sun Young Kim,
Sorin Draghici,
Pooja Mittal,
Juan Pedro Kusanovic,
Tinnakorn Chaiworapongsa,
Sonia S Hassan,
Chong Jai Kim
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ABSTRACT: This study was performed to assess the biological significance of miR-210 in preeclampsia and small-for-gestational-age (SGA) pregnancies. Placental miR-210 expression was evaluated by quantitative RT-PCR (RT-qPCR) in the following groups: i) appropriate-for-gestational-age pregnancies (n = 72), ii) preeclampsia (n = 52), iii) SGA (n = 66), and iv)preeclampsia with SGA (n = 31). The effects of hypoxia (1% O(2)) on miR-210 and iron-sulfur cluster scaffold homologue (ISCU) expressions and miR-210 binding to ISCU 3' UTR were examined in Swan 71 and BeWo cell lines. Perls' reaction (n = 229) and electron microscopy (n = 3) were conducted to verify siderosis of trophoblasts. miR-210 expression was increased in preeclampsia and SGA cases and was decreased with birth weight and gestational age. In both cell lines, miR-210 was induced by hypoxia, whereas ISCU expression was decreased. The luciferase assay confirmed miR-210 binding to ISCU mRNA 3' UTR. RNA interference knockdown of ISCU expression in Swan 71, but not in BeWo, cells resulted in autophagosomal and siderosomal iron accumulation and a fourfold decrease of Matrigel invasion (P = 0.004). Placental ISCU expression was decreased in preeclampsia (P = 0.002) and SGA (P = 0.002) cases. Furthermore, hemosiderin-laden trophoblasts were more frequent in the placental bed of preterm preeclampsia and/or SGA births than in control cases (48.7% versus 17.9%; P = 0.004). Siderosis of interstitial trophoblasts is a novel pathological feature of preeclampsia and SGA. The findings herein suggest that ISCU down-regulation by miR-210 perturbing trophoblast iron metabolism is associated with defective placentation.
American Journal Of Pathology 08/2011; 179(2):590-602. · 4.89 Impact Factor
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Giovanna Oggé,
Roberto Romero, Deug-Chan Lee,
Francesca Gotsch,
Nandor Gabor Than,
Joonho Lee,
Tinnakorn Chaiworapongsa,
Zhong Dong,
Pooja Mittal,
Sonia S Hassan,
Chong Jai Kim
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ABSTRACT: Acute chorioamnionitis of infectious origin and chronic chorioamnionitis of immunological origin are two major placental lesions of spontaneous preterm birth with elevated amniotic fluid interleukin-6 and CXCL10 concentrations, respectively. The changes in the amniotic fluid proteome associated with intra-amniotic infection and acute chorioamnionitis are well defined, yet alterations unique to chronic chorioamnionitis remain to be elucidated. This study was conducted to determine those amniotic fluid proteins changing specifically in the presence of chronic chorioamnionitis. Amniotic fluid obtained from acute chorioamnionitis, chronic chorioamnionitis and gestational age-matched controls were analysed by two-dimensional (2D) difference in gel electrophoresis and MALDI-TOF analyses. The type of histological inflammation was used to define each condition in preterm labour cases (n = 125) and term not in labour cases (n = 22), and the amniotic fluid concentrations of interleukin-6, CXCL8, CXCL10 and prostaglandin F(2α) were also measured by specific immunoassays. Among preterm labour cases, 31 differentially expressed proteins were identified in chronic chorioamnionitis cases as compared to both acute chorioamnionitis and control cases. Importantly, glycodelin-A, which maintains maternal tolerance against an allogeneic fetus, was decreased in chronic chorioamnionitis, while haptoglobin was increased. We report the amniotic fluid proteome of chronic chorioamnionitis for the first time, and the findings herein strongly suggest that there is a pathophysiological association between the changes of immunomodulatory proteins in the amniotic fluid and chronic chorioamnionitis, a histological manifestation of maternal anti-fetal allograft rejection.
The Journal of Pathology 03/2011; 223(4):553-65. · 6.32 Impact Factor
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Deug-Chan Lee,
Sonia S Hassan,
Roberto Romero,
Adi L Tarca,
Gaurav Bhatti,
Maria Teresa Gervasi,
Joseph A Caruso,
Paul M Stemmer,
Chong Jai Kim,
Lea Kirstine Hansen,
Naja Becher,
Niels Uldbjerg
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ABSTRACT: The cervical mucus plug (CMP) differs from the cervical secretions of non-pregnant women, and is the ultimate sealant of the uterine cavity during pregnancy. Although several studies have analyzed biochemical properties of large glycoproteins in the CMP, comprehensive information about its protein composition is yet unavailable. We hypothesized that protein profiling of the CMP could provide key clues to its physiological functions in pregnancy. For this purpose, five CMPs obtained from women in labor at term were analyzed by LC-MS/MS. Out of 291 total proteins identified, 137 were detected in two or more samples, which included S100A8, S100A9, and complement proteins (C3, C4a, C4b, C6, and C8g). Several proteins, which have not been described in the cervical mucus of non-pregnant women or in cervicovaginal fluids, such as CD81 antigen and pregnancy zone protein, were also identified. Gene ontology analysis of identified proteins showed significant enrichment of 28 biological processes such as 'activation of plasma proteins involved in acute inflammatory response' and 'positive regulation of cholesterol esterification'. We report the proteome of CMPs from pregnant women at term for the first time, and the overall findings strongly suggest an important role for the CMP in the maintenance of pregnancy and parturition.
Journal of proteomics 02/2011; 74(6):817-28. · 5.07 Impact Factor
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Pooja Mittal,
Roberto Romero,
Adi L Tarca,
Sorin Draghici,
Chia-Ling Nhan-Chang,
Tinnakorn Chaiworapongsa,
John Hotra,
Ricardo Gomez,
Juan Pedro Kusanovic, Deug-Chan Lee,
Chong Jai Kim,
Sonia S Hassan
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ABSTRACT: This study was undertaken to identify the molecular basis of an arrest of descent.
Human myometrium was obtained from women in term labor (TL; n = 29) and arrest of descent (AODes; n = 21). Gene expression was characterized using Illumina HumanHT-12 microarrays. A moderated Student t test and false discovery rate adjustment were applied for analysis. Confirmatory quantitative reverse transcription-polymerase chain reaction and immunoblot were performed in an independent sample set.
Four hundred genes were differentially expressed between women with an AODes compared with those with TL. Gene Ontology analysis indicated enrichment of biological processes and molecular functions related to inflammation and muscle function. Impacted pathways included inflammation and the actin cytoskeleton. Overexpression of hypoxia inducible factor-1a, interleukin -6, and prostaglandin-endoperoxide synthase 2 in AODes was confirmed.
We have identified a stereotypic pattern of gene expression in the myometrium of women with an arrest of descent. This represents the first study examining the molecular basis of an arrest of descent using a genome-wide approach.
American journal of obstetrics and gynecology 02/2011; 204(2):177.e15-33. · 3.28 Impact Factor
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ABSTRACT: Prostaglandin-endoperoxide synthase 2 (PTGS2) is a key enzyme involved in parturition. PTGS2 mRNA was found to be differentially expressed between placental amnion (amnion overlying the placental disc) and reflected amnion (amnion of the extraplacental chorioamniotic membranes) in term placentas.
The aim was to evaluate the spatial and temporal regulation of PTGS2 expression in the amnion and the chorion-decidua.
PTGS2 expression was analyzed in the amnion and chorion-decidua obtained from 32 women: term not in labor (n = 12), term in labor (n = 12), and preterm labor (n = 8), by immunoblotting and densitometry. Prostaglandin E(2) (PGE(2)) in the amnion and chorion-decidua was measured by a specific immunoassay.
Compared to preterm labor cases, PTGS2 expression increased at term before the onset of labor far more prominently in placental amnion (4.5-fold; P = 0.002) than in reflected amnion (1.4-fold; P = 0.007). There was a significant increase in PTGS2 expression in reflected amnion (2.9-fold; P < 0.01) but not in placental amnion with labor at term. PTGS2 expression was higher in reflected amnion than in chorion-decidua in labor at term (2.9-fold; P < 0.01). PTGS2 was barely detected in amnion and chorion-decidua with preterm labor. Expression of PGE(2) showed a good correlation with PTGS2 expression (r = 0.722; P < 0.001).
PTGS2 expression in the amnion shows a distinct spatial and temporal regulation. Spontaneous labor at term and pathological preterm labor clearly differ in amniotic PTGS2 and PGE(2) abundance. Our observations underscore the biological significance of the amnion and amniotic fluid in human parturition.
The Journal of clinical endocrinology and metabolism 09/2010; 95(9):E86-91. · 6.50 Impact Factor
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Deug-Chan Lee,
Roberto Romero,
Chong Jai Kim,
Tinnakorn Chaiworapongsa,
Adi L Tarca,
JoonHo Lee,
Yeon-Lim Suh,
Shali Mazaki-Tovi,
Edi Vaisbuch,
Pooja Mittal,
Sorin Draghici,
Offer Erez,
Juan Pedro Kusanovic,
Sonia S Hassan,
Jung-Sun Kim
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ABSTRACT: The mechanism of mouse parturition is thought to involve myometrial infiltration by amniotic fluid (AF) macrophages, activated by surfactant protein-A (SP-A). In humans, the concentration of AF SP-A decreases during labor, and no fetal macrophages are found in the myometrium after labor. Therefore, it appears that the mechanisms of labor in mice and humans are different. We investigated a potential role for SP-A in human pregnancy and parturition by examining SP-A expression patterns in AF and amnion. High molecular mass (>250 kDa) oligomeric SP-A was increased in AF with advancing gestation. Interestingly, these oligomers were more abundant in placental amnion before labor at term, while they increased primarily in reflected amnion during labor (p < 0.05). Immunoblotting showed a binding of high molecular mass SP-A in AF to amnion. In C57BL/6 mice, oligomeric SP-A was also readily detected in AF from E15 onwards, but not in amnion. Macrophage density in mice myometrium did not change with advancing gestational age. Microarray analysis of human amnion explants incubated with SP-A revealed a molecular signature of inhibited cytokine-cytokine receptor interaction with downregulation of IL-1beta, CXCL2, and CXCL5 mRNA expression. The findings in this study strongly suggest that SP-A signals amniotic anti-inflammatory response via AF during pregnancy. We propose that an SP-A interaction among AF, placental amnion, and reflected amnion is a unique mechanism for immunoregulation in human pregnancy akin to that established in lung biology. However, AF SP-A and fetal macrophages by themselves do not seem to be exclusive effectors of parturition in humans.
The Journal of Immunology 06/2010; 184(11):6479-91. · 5.79 Impact Factor
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Mi Jeong Kim,
Roberto Romero,
Maria Teresa Gervasi,
Jung-Sun Kim,
Wonsuk Yoo, Deug-Chan Lee,
Pooja Mittal,
Offer Erez,
Juan Pedro Kusanovic,
Sonia S Hassan,
Chong Jai Kim
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ABSTRACT: Acute chorioamnionitis is a response to amniotic fluid (AF) infection. However, it remains unclear whether substantial bacterial propagation in the chorioamniotic membranes (CAMs) precedes microbial invasion of the amniotic cavity (MIAC), which is inconsistent with characteristic 'amniotropic neutrophil migration' in acute chorioamnionitis. This study was performed to determine whether CAMs have widespread bacterial infection during MIAC and whether bacteria normally colonize CAMs. AF pellets and CAMs from the following groups were studied: group 1, patients with positive (n=18) or negative (n=22) AF cultures; group 2, patients with or without acute chorioamnionitis in which the amnion and chorion were studied separately (n=60); and group 3, patients at term who underwent a cesarean delivery (n=30). SYTO 9/propidium iodide fluorescent staining and fluorescent in situ hybridization for 16S rRNA were performed. Real-time quantitative PCR for 16S rDNA and PCR for genital mycoplasmas were also conducted. Bacteria were more frequently detected in AF than in CAMs of patients with positive AF culture (100 vs. 33%; P<0.0001). Bacteria were detected more frequently in CAMs as the severity of chorioamnionitis increased (P<0.01). The median 16S rRNA gene copy number in the amnion was significantly greater than in the chorion (group 2; P<0.0001). Bacteria were not detected in CAMs or AF in women at term before labor (group 3). A fraction of patients with chorioamnionitis or MIAC did not have bacteria in CAMs. Collectively, the findings herein indicate that MIAC does not follow widespread infection of CAMs, but precedes it. We propose a model of MIAC: the initial stage is intra-amniotic bacterial invasion through a discrete region of the CAMs, followed by intra-amniotic proliferation, and bacterial invasion of CAMs primarily extends from the amniotic fluid. This study emphasizes the importance of assessing the intra-amniotic compartment for diagnosis and treatment of preterm birth.
Laboratory Investigation 06/2009; 89(8):924-36. · 3.64 Impact Factor
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Mi Jeong Kim,
Roberto Romero,
Chong Jai Kim,
Adi L Tarca,
Sovantha Chhauy,
Christopher LaJeunesse, Deug-Chan Lee,
Sorin Draghici,
Francesca Gotsch,
Juan Pedro Kusanovic,
Sonia S Hassan,
Jung-Sun Kim
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ABSTRACT: The co-presence of histoincompatible fetal and maternal cells is a characteristic of human placental inflammation. Villitis of unknown etiology (VUE), a destructive inflammatory lesion of villous placenta, is characterized by participation of Hofbauer cells (placental macrophages) and maternal T cells. In contrast to acute chorioamnionitis of infection-related origin, the fundamental immunopathology of VUE is unknown. This study was performed to investigate the placental transcriptome of VUE and to determine whether VUE is associated with systemic maternal and/or fetal inflammatory response(s). Comparison of the transcriptome between term placentas without and with VUE revealed differential expression of 206 genes associated with pathways related to immune response. The mRNA expression of a subset of chemokines and their receptors (CXCL9, CXCL10, CXCL11, CXCL13, CCL4, CCL5, CXCR3, CCR5) was higher in VUE placentas than in normal placentas (p < 0.05). Analysis of blood cell mRNA showed a higher expression of CXCL9 and CXCL13 in the mother, and CXCL11 and CXCL13 in the fetus of VUE cases (p < 0.05). The median concentrations of CXCL9, CXCL10, and CXCL11 in maternal and fetal plasma were higher in VUE (p < 0.05). Comparison of preterm cases without and with acute chorioamnionitis revealed elevated CXCL9, CXCL10, CXCL11, and CXCL13 concentrations in fetal plasma (p < 0.05), but not in maternal plasma with chorioamnionitis. We report for the first time the placental transcriptome of VUE. A systemic derangement of CXC chemokines in maternal and fetal circulation distinguishes VUE from acute chorioamnionitis. We propose that VUE be a unique state combining maternal allograft rejection and maternal antifetal graft-vs-host disease mechanisms.
The Journal of Immunology 03/2009; 182(6):3919-27. · 5.79 Impact Factor
