Preterm birth is a worldwide health concern accounting for 11.1% of all births. It is linked to adverse outcomes including cerebral palsy and chronic lung disease. Parturition is associated with marked inflammation in the gestational tissues with the myometrium being the key effector, responsible for coordinated contractions that lead to delivery of the fetus. Despite multiple theories, the mechanism underlying the onset of human labour remains unclear. As there is currently no effective method in stopping labour once the process has begun, research is focused on prevention. Currently, the only drug agent with proven efficacy is progesterone (P4), which has been shown to reduce the incidence of preterm labour (PTL) by up to 40%. P4 is known to have anti-inflammatory action, however its mode of action in the context of reducing the rate of PTL remains unclear. The overall aim of this project was to further understand the mechanism of P4 action in order to facilitate the development of superior drugs to combat PTL. Using a pregnant murine model, my studies have shown that vehicle control labour is associated with inflammation. Further, P4 supplementation was sufficient to delay labour by at least two days in association with a delay in inflammation and a loss of the rise in contraction-associated proteins including connexin-43. A second pregnant murine model was used to block P4 action with the mixed progesterone receptor (PR) and glucocorticoid receptor antagonist mifepristone (RU486), with animals delivering preterm at 17.4 ± 0.35 hours post administration. A pre-delivery (9 hours post RU486) significant up-regulation of the contraction-associated proteins connexin-43 and oxytocin receptor was observed in association with a peak in p65 and p38 phosphorylation. Inflammatory cytokines, such as IL-6, peaked at the time of labour at the RNA level and demonstrated a bimodal peak at the protein level (9 hours and labour). Much of the in vitro work on myometrial function is hampered by a lack of physiological relevance due low PR levels and the requirement for treatment with high P4 doses. In order to address this, I have developed and validated via microarray a myometrial explant model to study P4 function. Subsequently, I have shown that, in this model, P4 signals via PR and that this is associated with a reduction in p65 and c-Jun phosphorylation in an IL-1β-driven model of inflammation. I have also shown that in explants obtained from labouring patients, P4 does not lose the ability to repress inflammation. Finally, several authors have proposed a variety of mechanisms to account of the functional withdrawal of P4 in human parturition. In order to investigate some of these further, I have used the group's myometrial tissue bank. I have shown that myometrial P4 levels do not change with labour onset and confirmed other groups' reports that term labour is associated with a shift to PR-A dominance. I went on to show that, compared with idiopathic preterm labour, preterm labour secondary to chorioamnionitis is associated with a significant reduction in nuclear receptor corepressor (NCoR) and steroid receptor coactivator 1 (SRC1), as well as a significant increase in heat-shock protein 90 (HSP90) and FK506-binding protein 51 (FKBP51). Additionally, I demonstrated that preterm labour in twins is associated with a significant up-regulation of NCoR. In summary, the findings of this thesis broaden our understanding of P4 function and will help drive the field of parturition and PTL forward.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:702844 |
| Date | January 2016 |
| Creators | Georgiou, Ektoras |
| Contributors | Johnson, Mark ; Sooranna, Dev |
| Publisher | Imperial College London |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://hdl.handle.net/10044/1/44073 |
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