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Title: The role of pro-resolution mediators in human parturition
Author: Golightly, Ellen
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2012
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Preterm labour and dysfunctional term labour lead to the most pre-eminent problems in obstetric practice today. We currently lack effective strategies for preventing spontaneous preterm labour, and prematurity remains the leading cause of perinatal morbidity and mortality. In contrast, some women do not labour effectively at term, or pregnancy becomes prolonged, both of which increase the risk of caesarean section, rates of which are on the rise in this country. Human labour is an inflammatory process, characterised by an influx of inflammatory cells into the myometrium and cervix at the onset of labour, and an increase in production of proinflammatory cytokines and expression of cell adhesion molecules. A substantial body of evidence has now accumulated in support of this theory, but relatively little attention has yet focused on anti-inflammatory pathways within this process. The resolution of inflammation is now recognised to be an active process, driven by a variety of endogenous pro-resolution factors. These include the lipid mediator lipoxin A4 (LXA4), derived from arachidonic acid and signalling through a G-protein coupled receptor, a member of the formyl peptide receptor family, FPR2/ALX. Another is Annexin A1 (ANXA1), a glucocorticoid-regulated peptide that also signals via FPR2/ALX. The aim of this thesis was to explore the role of these anti-inflammatory and pro-resolution mediators in myometrial and placental tissues and examine what role they may have within the inflammatory process of labour. Expression of the receptor FPR2/ALX and enzymes involved in the synthesis of LXA4 was determined by quantitative RT-PCR in labouring and non-labouring tissues of the reproductive tract and FPR2/ALX was localised in these tissues using immunohistochemistry. It was found that expression of the receptor and the enzyme 5-lipoxygenase (ALOX5) were upregulated in labouring tissues and that the receptor localised primarily to immune cells. A microarray and functional genomics were used to examine inflammation in myometrium and interesting parallels were drawn between artificially-induced inflammation and the process of labour, identifying pathways of interest for further study. Myometrial tissue was cultured in hypoxia, a pro-inflammatory environment, and it was demonstrated by ELISA and quantitative RT-PCR that LXA4 production was unaffected in these conditions, but that there may be changes in expression of ALOX5 and FPR2/ALX. Quantitative RT-PCR and immunohistochemistry were used to explore the expression of ANXA1 in labouring and non-labouring tissues and found localisation to immune cells and vascular endothelial cells but no difference in expression in labour. Tissue culture and quantitative RT-PCR demonstrated glucocorticoidregulation of FPR2/ALX but not ANXA1 in myometrium. This work has shown that LXA4 and ANXA1 are present in the reproductive tract during pregnancy and parturition and that a mechanism may exist, via upregulation of their common receptor, for a role within the inflammatory process of labour. Further work will aim to clarify the nature of this role and its functional effects, with the ultimate aim of better understanding the process of inflammation during parturition leading to the development of strategies to prevent or treat preterm and dysfunctional term labour.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available