Denison, Fiona Charlotte

2018-01-31T11:19:47Z

2018-01-31T11:19:47Z

2000

Pregnancy and parturition necessitate profound alterations in the maternal immune response likely effected by paracrine interactions between inflammatory mediators, hormones and various local factors. However, the nature of these interactions and how they effect the recognition and maintenance of pregnancy and initiation of parturition are not well understood. The aim of this thesis was to investigate the role of inflammatory mediators, specifically cytokines, prostaglandin E2 (PGE2), nitric oxide (NO), metalloproteinases (MMPs) and their endogenous inhibitors (TIMPs) during pregnancy and parturition.

Part 1) This investigated the roles of inflammatory mediators in the initiation and maintenance of pregnancy. The role of seminal plasma, specifically its component PGs (PGE2 and 19- hydroxy PG), in the initial adaptation of the maternal immune response to pregnancy was studied in the non-pregnant cervix, peripheral blood and a monocyte cell line. PGs stimulated release of IL-10, thus favouring development of a T-helper (Th)-2 type, pregnancy favourable immune response. They also stimulated release of the neutrophil chemotactic factor IL-8, which may be involved in mediating post-coital cervical leukocytosis. Furthermore, peripheral blood from pregnant women, specifically the mononuclear cell (CD14+) fraction, released significantly more monocyte chemotactic peptide-1 (MCP-1), which also favours a Th-2 type immune response, than that from non-pregnant women. Release of IL-8 and regulated on activation and normally T-cell expressed and secreted (RANTES) was comparable between groups. The concentrations of MCP-1, IL-8 and RANTES in the fluid compartments within the first trimester uterus were also examined. The chemokines were differentially distributed with MCP-1 and IL- 8 being present in amniotic fluid, maternal serum and extra-embryonic coelom with highest levels of both in the latter compartment. RANTES was only detectable in peripheral serum. These findings support the hypothesis that inflammatory mediators are important in the initiation and maintenance of pregnancy and may play a role in early placental and fetal development.

Part 2) This examined the involvement and regulation of inflammatory mediators in cervical ripening and parturition. Cervical ripening involves tissue remodelling mediated by inflammatory mediators, infiltrating cells, MMPs and TIMPs. However their regulation in the cervix are not well understood. In the non-pregnant cervix, IL-8 release was stimulated by PGE2 and NO and inhibited by dexamethasone and progesterone. In addition, the anti-inflammatory factor secretory leukocyte protease inhibitor was stimulated by progesterone and inhibited by PGE2 and PGE2 release was stimulated by NO. In addition, MMP-2 and -9 and TIMPs-1 and -4 were released by the non-pregnant cervix but this secretion was not affected by in vitro administration of PGE2 or NO. Withdrawal of progesterone, which is essential for pregnancy maintenance, also initiates cervical ripening by unknown mechanisms. In vivo administration of the anti-gestogen mifepristone increased protein expression of MMP-1, -8 and -9, CD45 (leukocyte common antigen), neutrophil elastase and CD68 (monocyte marker) but not MMP-2, TIMP-1, -2 and -4 in the first trimester cervix as detected by immunohistochemistry. To summarise the cervical studies, the non-pregnant and pregnant cervix are capable of releasing a wide range of inflammatory mediators, MMPs and TIMPs, co-ordination of which may mediate cervical ripening. Next, the release and regulation of inflammatory mediators at the materno-fetal interface were investigated. MCP-1, IL-8, RANTES and IL-10 were released by third trimester amnion, chorion, decidua and placenta with secretion of MCP-1, IL-8 and IL-10 but not RANTES being stimulated by PGE2 in a perfused placental cotyledon system. Secretory leukocyte protease inhibitor was released predominantly by decidua and was present in increasing concentrations within amniotic fluid during pregnancy and labour. Cytokines may play a role in the inflammatory process of parturition, PGE2 may play an important immunomodulatory role within the placenta at term and secretory leukocyte protease inhibitor might act both to limit the pro¬ inflammatory cascades ongoing during parturition and to protect against microbial invasion. To summarise this section, inflammatory mediators are important in the initiation and regulation of cervical ripening and parturition with complex interactions occurring within the cervix and at the feto-maternal interface.

http://hdl.handle.net/1842/26441

The University of Edinburgh

Annexe Thesis Digitisation Project 2017 Block 15

Inflammatory mediators : their roles during pregnancy and parturition

Thesis or Dissertation

Doctoral

MD Doctor of Medicine