Obstetrics and Gynaecology - Research Publications

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    NOD1 and NOD2 Regulate Proinflammatory and Prolabor Mediators in Human Fetal Membranes and Myometrium via Nuclear Factor-Kappa B
    Lappas, M (OXFORD UNIV PRESS INC, 2013-07)
    Preterm birth remains one of the most important issues facing perinatal medicine today, with chronic inflammation and/or infection being the biggest etiological factor. The nucleotide oligomerization domain (NOD) intracellular molecules recognize a wide range of microbial products as well as other intracellular danger signals, thereby initiating inflammation through activation of nuclear factor KB (NFKB), a central regulator of the terminal processes of human labor and delivery. The aims of this study were to determine the effect of 1) human labor, proinflammatory cytokines, and bacterial endotoxin LPS on NOD1 and NOD2 expression and 2) NOD1 and NOD2 activation on the expression of prolabor mediators in human fetal membranes and myometrium. NOD1 and NOD2 expression was significantly higher in fetal membranes and myometrium after spontaneous labor when compared to nonlaboring tissues. Bacterial endotoxin LPS and the proinflammatory cytokines TNF and IL1B significantly increased NOD2, but not NOD1, expression. Furthermore, LPS-induced NOD2 expression was decreased by the NFKB inhibitor BAY 11-7082. In both fetal membranes and myometrium, the NOD1 ligand bacterial iE-DAP and the NOD2 ligand bacterial MDP significantly increased the expression and secretion of proinflammatory cytokines (IL6 and IL8), cyclooxygenase (PTGS2) expression and subsequent release of prostaglandins PGE2 and PGF2alpha, and the expression and activity of MMP9. The effects of these NOD1 and NOD2 ligands were mediated via NFKB, as 1) both iE-DAP and MDP significantly increased NFKB activation and 2) the NFKB inhibitor BAY 11-7082 attenuated iE-DAP- and MDP-induced expression and secretion of prolabor mediators. In conclusion, NOD1 and NOD2 are increased in laboring fetal membranes and myometrium and with bacterial infection. Agonist activation of NOD1 and NOD2 by bacterial products leads to NFKB activation and transcription of NFKB induced prolabor genes. NOD1 and NOD2 may thus represent therapeutic targets for the treatment and/or management of preterm birth.
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    Dietary phytophenols curcumin, naringenin and apigenin reduce infection-induced inflammatory and contractile pathways in human placenta, foetal membranes and myometrium
    Lim, R ; Barker, G ; Wall, CA ; Lappas, M (OXFORD UNIV PRESS, 2013-07)
    A tenet of contemporary obstetrics is that a significant proportion of preterm births involve bacterial infection. Bacterial endotoxin induces pro-inflammatory cytokines, prostaglandins and proteases via the pro-inflammatory pathway nuclear factor-κB (NF-κB), which plays a key role in initiating uterine contractions and rupture of foetal membranes. In non-gestational tissues, the phytophenols curcumin, naringenin and apigenin exert anti-inflammatory properties via inhibition of NF-κB. The aim of this study was to determine whether these treatments regulate pro-inflammatory and pro-labour mediators in human gestational tissues. Placenta, foetal membranes and myometrium were treated with curcumin, naringenin and apigenin in the presence of lipopolysaccharide (LPS) or interleukin (IL)-1β. In placenta and foetal membranes, all treatments significantly reduced LPS-stimulated release and gene expression of pro-inflammatory cytokines IL-6 and IL-8; placenta decreased cyclooxygenase (COX-2) mRNA expression, subsequent release of prostaglandins PGE2 and PGF2α and expression and activity of matrix-degrading enzyme matrix metalloproteinase (MMP)-9. In myometrial cells, all treatments attenuated IL-1β-induced COX-2 expression, release of PGE2 and PGF2α and expression and activity of MMP-9. Although naringenin significantly attenuated IL-1β-induced IL-6 and IL-8 mRNA expression and release, there was no effect of curcumin and apigenin. LPS-stimulated release of 8-isoprostane, a marker of oxidative stress, was attenuated by all treatments. NF-κB p65 DNA-binding activity was also decreased using these treatments. In conclusion, curcumin, naringenin and apigenin exert anti-inflammatory properties in human gestational tissues by inhibiting the transcriptional activity of NF-κB. Further studies should be undertaken to define a possible implication of these natural spices in the management of preterm labour and delivery.
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    A Novel Role for FOXO3 in Human Labor: Increased Expression in Laboring Myometrium, and Regulation of Proinflammatory and Prolabor Mediators in Pregnant Human Myometrial Cells
    Lim, R ; Barker, G ; Lappas, M (OXFORD UNIV PRESS INC, 2013-06)
    Preterm birth is the leading factor causing neonatal mortality and morbidity. Inflammation plays a central role in stimulating uterine contractility, which is responsible for approximately one-third of all preterm births. Recent studies have shown that the transcription factor Forkhead box O3 (FOXO3) regulates inflammation in nongestational tissues such as adipocytes and hepatocytes. Thus, in this study, we sought to determine the effect of 1) human term labor on myometrial FOXO3 expression and 2) FOXO3 inhibition and FOXO3 overexpression on proinflammatory and prolabor mediators in human myometrial cells. Higher FOXO3 gene and protein expression were detected in myometrium obtained from women in labor when compared to samples taken from nonlaboring women. Myometrial cells were isolated from pregnant human myometrium, and FOXO3 silencing was achieved using siRNA and overexpression using a cDNA clone. We found that the loss of FOXO3 in myometrial cells was associated with a significant decrease in IL1B-induced IL6 and IL8 expression and production, cyclooxygenase ([COX]-2, official symbol PTGS2) expression and subsequent prostaglandin (PGE2 and PGF2alpha) release, and matrix metalloproteinase 9 (MMP9) and mRNA expression and activity. Conversely, FOXO3 overexpression increased cytokine expression and secretion, prostaglandin production, and MMP9 expression in myometrial cells treated with IL1B. In summary, we have identified FOXO3 as an upstream mediator of inflammation in human myometrium. Thus, FOXO3 may present an alternative therapeutic target for preventing preterm birth and its associated morbidity and mortality.
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    Complement C5a Regulates Prolabor Mediators in Human Placenta
    Lappas, M ; Woodruff, TM ; Taylor, SM ; Permezel, M (OXFORD UNIV PRESS INC, 2012-06)
    Human preterm and term parturition is associated with inflammatory cascades in the uteroplacental unit. Activation of the complement cascade releases potent proinflammatory mediators, including the anaphylatoxin C5a, which exerts its biological effects through its receptors, C5AR (also known as CD88) and C5L2, official symbol GPR77. To date, there are few data available on the role of C5a and CD88 in human pregnancy, so the aim of this study was to determine the effect of C5a and CD88 on some key inflammatory pathways involved in human parturition. Placental tissue samples were obtained from normal pregnancies at the time of Cesarean section. Human placental and fetal membranes were incubated in the absence (basal control) or presence of 0.5 μg/ml (~60 nM) human recombinant C5a for 24 h. Concentrations of proinflammatory cytokines, prostaglandins, and 8-isoprostane (a marker of oxidative stress) were quantified by ELISA and secretory matrix metalloproteinases (MMPs) activity by zymography. NFKB DNA binding activity and NFKBIA (IkappaB-alpha; inhibitor of NFKB) protein degradation were analyzed by ELISA and Western blotting, respectively. In the presence of C5a, proinflammatory cytokines (IL6 and IL8), cyclooxygenase (COX)-2; official symbol PTGS2) expression, and subsequent prostaglandin (PGE(2) and PGF(2alpha)), MMP9 enzyme production, and NFKB DNA activation were all significantly increased. The C5a-induced prolabor responses were significantly reduced by treatment with the selective CD88 antagonist PMX53 and the NFKB inhibitor BAY 11-7082. We conclude that C5a upregulates prolabor mediators in human gestational tissues via CD88-mediated NFKB activation.
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    2D-DIGE to identify proteins associated with gestational diabetes in omental adipose tissue
    Oliva, K ; Barker, G ; Rice, GE ; Bailey, MJ ; Lappas, M (BIOSCIENTIFICA LTD, 2013-08)
    Gestational diabetes mellitus (GDM) is a significant risk factor for the type 2 diabetes epidemic in many populations. Maternal adipose tissue plays a central role in the pathophysiology of GDM. Thus, the aim of this study was to determine the effect of GDM on the proteome of adipose tissue. Omental adipose tissue was obtained at the time of term Caesarean section from women with normal glucose tolerance (NGT) or GDM. 2D-difference gel electrophoresis (DIGE), followed by mass spectrometry, was used to identify protein spots (n = 6 patients per group). Western blotting was used for confirmation of six of the spot differences (n = 6 patients per group). We found 14 proteins that were differentially expressed between NGT and GDM adipose tissue (≥ 1.4-fold, P < 0.05). GDM was associated with an up-regulation of four proteins: collagen alpha-2(VI) chain (CO6A2 (COL6A2)), fibrinogen beta chain (FIBB (FGB)), lumican (LUM) and S100A9. On the other hand, a total of ten proteins were found to be down-regulated in adipose tissue from GDM women. These were alpha-1-antitrypsin (AIAT (SERPINA 1)), annexin A5 (ANXA5), fatty acid-binding protein, adipocyte (FABP4), glutathione S-transferase P (GSTP (GSTP1)), heat-shock protein beta-1 (HSP27 (HSPB1)), lactate dehydrogenase B chain (LDHB), perilipin-1 (PLIN1), peroxiredoxin-6 (PRX6 (PRDX6)), selenium-binding protein 1 (SBP1) and vinculin (VINC (VCL)). In conclusion, proteomic analysis of omental fat reveals differential expression of several proteins in GDM patients and NGT pregnant women. This study revealed differences in expression of proteins that are involved in inflammation, lipid and glucose metabolism and oxidative stress and added further evidence to support the role of visceral adiposity in the pathogenesis of GDM.