Inflammatory pathways in the mechanism of parturition

Increasing evidence suggests that parturition is an inflammatory process. In this brief overview, inflammatory events occurring in association with parturition, and the mechanism by which they may contribute to labour and delivery will be discussed. Mention will be made of how this information may be of use in regulating the timing and the onset of parturition

A translational approach to studying preterm labour

Preterm labour continues to be a major contributor to neonatal and infant morbidity. Recent data from the USA indicate that the number of preterm deliveries (including those associated with preterm labour) has risen in the last 20 years by 30%. This increase is despite considerable efforts to introduce new therapies for the prevention and treatment of preterm labour and highlights the need to assess research in this area from a fresh perspective. In this paper we discuss i) the limitations of our knowledge concerning prediction, prevention and treatment of preterm labour and ii) future multidisciplinary strategies for improving our approach

Cervical epithelial damage promotes Ureaplasma parvum ascending infection, intrauterine inflammation and preterm birth induction in mice

Around 40% of preterm births are attributed to ascending intrauterine infection, and Ureaplasma parvum (UP) is commonly isolated in these cases. Here we present a mouse model of ascending UP infection that resembles human disease, using vaginal inoculation combined with mild cervical injury induced by a common spermicide (Nonoxynol-9, as a surrogate for any mechanism of cervical epithelial damage). We measure bacterial load in a non-invasive manner using a luciferase-expressing UP strain, and post-mortem by qPCR and bacterial titration. Cervical exposure to Nonoxynol-9, 24 h pre-inoculation, facilitates intrauterine UP infection, upregulates pro-inflammatory cytokines, and increases preterm birth rates from 13 to 28%. Our results highlight the crucial role of the cervical epithelium as a barrier against ascending infection. In addition, we expect the mouse model will facilitate further research on the potential links between UP infection and preterm birth

Transcription analysis of the myometrium of labouring and non-labouring women

An incomplete understanding of the molecular mechanisms that initiate normal human labour at term seriously hampers the development of effective ways to predict, prevent and treat disorders such as preterm labour. Appropriate analysis of large microarray experiments that compare gene expression in non-labouring and labouring gestational tissues is necessary to help bridge these gaps in our knowledge. In this work, gene expression in 48 (22 labouring, 26 non-labouring) lower-segment myometrial samples collected at Caesarean section were analysed using Illumina HT-12 v4.0 BeadChips. Normalised data were compared between labouring and non-labouring groups using traditional statistical methods and a novel network graph approach. We sought technical validation with quantitative real-time PCR, and biological replication through inverse variance-weighted meta-analysis with published microarray data. We have extended the list of genes suggested to be associated with labour: Compared to non-labouring samples, labouring samples showed apparent higher expression at 960 probes (949 genes) and apparent lower expression at 801 probes (789 genes) (absolute fold change ≥1.2, rank product percentage of false positive value (RP-PFP) <0.05). Although half of the women in the labouring group had received pharmaceutical treatment to induce or augment labour, sensitivity analysis suggested that this did not confound our results. In agreement with previous studies, functional analysis suggested that labour was characterised by an increase in the expression of inflammatory genes and network analysis suggested a strong neutrophil signature. Our analysis also suggested that labour is characterised by a decrease in the expression of muscle-specific processes, which has not been explicitly discussed previously. We validated these findings through the first formal meta-analysis of raw data from previous experiments and we hypothesise that this represents a change in the composition of myometrial tissue at labour. Further work will be necessary to reveal whether these results are solely due to leukocyte infiltration into the myometrium as a mechanism initiating labour, or in addition whether they also represent gene changes in the myocytes themselves. We have made all our data available at www.ebi.ac.uk/arrayexpress/ (accession number E-MTAB-3136) to facilitate progression of this work

Leukocyte density and proinflammatory mediator expression in regional human fetal membranes and decidua before and during labor at term

OBJECTIVES: The region of fetal membranes overlying the cervix, known as the zone of altered morphology (ZAM), is considered to be the principle site of membrane inflammatory activity and extracellular matrix remodelling. We wished to quantify the relative contribution of each area of fetal membranes to the inflammatory process of parturition. Specifically, we aimed to quantify and compare (1) leukocyte densities in three regions of fetal membranes and decidua before and during spontaneous labor at term, and (2) mRNA expression of interleukin (IL)-1 beta, IL-6, IL-8, cyclo-oxygenase type 1 (COX-1), and COX-2 in three regions of fetal membranes and decidua before and during spontaneous labor at term. METHODS: Biopsies of fetal membranes and decidua were obtained from pregnant women delivered by cesarean section at term both before and during spontaneous labor (n = 8 both groups). Fetal membranes were sampled from three areas, the ZAM, midzone (MZ), and periplacental (PP) regions. Leukocytes were identified by immunohistochemistry and their density quantified. Inflammatory mediator expression was quantified using TaqMan technology (Applied Biosystems, Foster City, CA). RESULTS: There was a significantly greater density of leukocytes in (1) the PP region of membranes compared with the ZAM, and (2) the decidua compared with amnion, amniotic connective tissue, and chorion. IL-1 beta, IL-6, and IL-8 mRNA expression was significantly greater in all regions following spontaneous labor compared with nonlaboring tissues. There were no regional differences in cytokine expression within the fetal membranes. Choriodecidua expressed significantly more IL-1 beta mRNA than amnion. Amnion expressed more COX-2 mRNA than choriodecidua. CONCLUSIONS: All regions of fetal membranes and decidua contribute to the inflammatory process of human parturition; however, their relative contributions differ in magnitude. Although the ZAM may be specifically important for membrane rupture, it does not appear to play a key or exclusive role in the other inflammatory processes of parturition. When studying fetal membranes, it is relevant to identify and define the area sampled for consistency and comparison with other studies