Obstetrics and Gynaecology - Research Publications
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ItemHuman cervicovaginal fluid biomarkers to predict term and preterm labor(FRONTIERS MEDIA SA, 2015-05-13)Preterm birth (PTB; birth before 37 completed weeks of gestation) remains the major cause of neonatal morbidity and mortality. The current generation of biomarkers predictive of PTB have limited utility. In pregnancy, the human cervicovaginal fluid (CVF) proteome is a reflection of the local biochemical milieu and is influenced by the physical changes occurring in the vagina, cervix and adjacent overlying fetal membranes. Term and preterm labor (PTL) share common pathways of cervical ripening, myometrial activation and fetal membranes rupture leading to birth. We therefore hypothesize that CVF biomarkers predictive of labor may be similar in both the term and preterm labor setting. In this review, we summarize some of the existing published literature as well as our team's breadth of work utilizing the CVF for the discovery and validation of putative CVF biomarkers predictive of human labor. Our team established an efficient method for collecting serial CVF samples for optimal 2-dimensional gel electrophoresis resolution and analysis. We first embarked on CVF biomarker discovery for the prediction of spontaneous onset of term labor using 2D-electrophoresis and solution array multiple analyte profiling. 2D-electrophoretic analyses were subsequently performed on CVF samples associated with PTB. Several proteins have been successfully validated and demonstrate that these biomarkers are associated with term and PTL and may be predictive of both term and PTL. In addition, the measurement of these putative biomarkers was found to be robust to the influences of vaginal microflora and/or semen. The future development of a multiple biomarker bed-side test would help improve the prediction of PTB and the clinical management of patients.
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ItemEffect of Supracervical Apposition and Spontaneous Labour on Apoptosis and Matrix Metalloproteinases in Human Fetal Membranes(HINDAWI LTD, 2013)BACKGROUND: Apoptosis and matrix metalloproteinase (MMP-9) are capable of hydrolysing components of the extracellular matrix and weakening the fetal membranes which leads to eventual rupture, a key process of human parturition. The aim of this study was to determine the effect of supracervical apposition and spontaneous labour on apoptosis and MMP-9 in human fetal membranes at term. METHODS: Fetal membranes were obtained from term non-labouring supracervical site (SCS) and compared to (i) a paired distal site (DS) or (ii) site of rupture (SOR) after spontaneous labour onset. RESULTS: The expression of the proapoptotic markers Bax, Smac, Fas, FasL, caspase-3, and PARP, was significantly higher in the non-labouring SCS chorion compared to paired DS. Bax, Smac, FasL, caspase-3, and PARP staining was higher in the non-labouring SCS fetal membranes than that in the post-labour SOR. MMP-9 expression and activity were higher in the post-labour SOR fetal membranes compared to non-labouring SCS fetal membranes. CONCLUSION: Components of the apoptotic signalling pathways and MMP-9 may play a role in rupture and labour. Non-labouring SCS fetal membranes display altered morphology and altered apoptotic biochemical characteristics in preparation for labour, while the laboured SOR displays unique MMP characteristics.
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ItemRelease of proinflammatory cytokines and 8-isoprostane from placenta, adipose tissue, and skeletal muscle from normal pregnant women and women with gestational diabetes mellitus(ENDOCRINE SOC, 2004-11)The aim of this study was to 1) profile the basal release of TNF-alpha, IL-6, IL-8, and 8-isoprostane (a marker of oxidative stress); and 2) investigate the effect of stimulation on the release of cytokines from sc adipose tissue and skeletal muscle from normal pregnant women and women with gestational diabetes mellitus (GDM). Placenta, sc adipose tissue, and skeletal muscle were incubated in the absence (control) or presence of lipopolysaccharide (LPS; 10 microg/ml), TNF-alpha (10 ng/ml), IL-6 (10 ng/ml), or IL-8 (10 ng/ml). After an 18-h incubation, the medium was collected, and the release of TNF-alpha, IL-6, IL-8, and 8-isoprostane was quantified by ELISA. In all three tissues, 8-isoprostane release was greater in women with GDM, and stimulation with LPS increased 8-isoprostane release from adipose and skeletal muscle, but not placenta, obtained from women with GDM. However, in tissues obtained from normal pregnant women, LPS stimulation increased 8-isoprostane release in placenta and had no effect in adipose tissue and skeletal muscle. Their was no difference in the release of TNF-alpha, IL-6, and IL-8 from placenta, adipose tissue, and skeletal muscle obtained from normal pregnant women and women with GDM. Stimulation of placenta, adipose tissue, and skeletal muscle with LPS and TNF-alpha resulted in greater release of IL-6 and IL-8, whereas only LPS increased TNF-alpha release from all three tissues. The data presented in this study demonstrate that there is a differential release of 8-isoprostane from fetal (placenta) and maternal (adipose tissue and skeletal muscle) tissues obtained from normal pregnant women and women with GDM. These data are consistent with the hypothesis that oxidative stress may be involved in the progression and/or pathogenesis of GDM.
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ItemN-acetyl-cysteine inhibits phospholipid metabolism, proinflammatory cytokine release, protease activity, and nuclear factor-κB deoxyribonucleic acid-binding activity in human fetal membranes in vitro(ENDOCRINE SOC, 2003-04)The production of reactive oxygen species (ROS), prostaglandins (PGs), proinflammatory cytokines, and proteases has been implicated in the pathogenesis of term and preterm labor. The nuclear factor-kappaB (NF-kappaB) transcription pathway is activated by ROS and is a key regulator of PGs, proinflammatory cytokine release, and protease activity. N-Acetyl-cysteine (NAC) is an antioxidant that through its ability to scavenger ROS suppresses NF-kappaB DNA-binding activity and resultant gene expression. The aim of this study was to elucidate the effect of NAC on NF-kappaB DNA-binding activity, phospholipid metabolism, cytokine release, and protease activity from human fetal membranes. Human amnion and choriodecidua (n = 9 separate placentas) were treated with 0 (control), 5, 10, or 15 mM NAC in the presence of 10 micro g/ml lipopolysaccharide. After 6-h incubation, the tissues were collected, NF-kappaB DNA binding activity was assessed by gel shift binding assays, and matrix metalloproteinase-9 and urokinase-type plasminogen activator activity were determined by zymography. The incubation medium was collected and assayed for type II phospholipase A(2) tissue content, IL-6, IL-8, TNFalpha, and 8-isoprostane release by ELISA. The release of PGF(2alpha) was measured by RIA. Treatment of fetal membranes with NAC significantly suppressed lipopolysaccharide-stimulated type II phospholipase A(2) release and content; PGF(2alpha), IL-6, IL-8, TNFalpha, and 8-isoprostane release; and matrix metalloproteinase-9 and urokinase-type plasminogen activator enzyme activity and suppressed NF-kappaB DNA-binding activity (by ANOVA, P < 0.05). The data presented in this study demonstrate that NAC inhibits an NF-kappaB-activated pathway and subsequent phospholipid metabolism, proinflammatory cytokine release, and protease activity in human fetal membranes.