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Title: Leukocyte trafficking dynamics in the regulation of labour
Author: Edey, Lydia
ISNI:       0000 0004 5920 9511
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2016
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Late gestation and labour is associated with inflammatory changes in the myometrium that include an increase in neutrophil and monocyte numbers. The mechanisms regulating altered leukocyte dynamics in pregnancy are not well understood, but may be critical in identifying novel targets for the prevention of preterm labour (PTL). PTL is defined as the onset of labour prior to 37 weeks gestation and often results in preterm birth (PTB). Here we investigated local and systemic leukocyte trafficking during late gestation and labour, focussing on the pro-inflammatory Ly-6Chigh monocyte subpopulation in mouse models of normal, preterm and delayed labour. Using flow cytometry and in vivo cell labelling methods, we demonstrated for the first time that blood-derived Ly-6Chigh monocyte densities increase in the myometrium prior to labour onset. Increases were also observed in the pools of intravascular, lung-marginated Ly-6Chigh monocytes and neutrophils during late gestation, which although not mirrored in the circulation is indicative of a systemic inflammatory response. Using exogenous progesterone supplementation and a progesterone receptor antagonist, we demonstrated that progesterone controls Ly-6Chigh monocyte cell densities within the myometrium, with rapid increases following its functional withdrawal. In a mouse model of infection-induced PTL by laparotomy and intrauterine LPS injection, we unexpectedly found that inflammatory leukocyte migration to the myometrium was low pre- labour. Levels of cytokines and chemokines, including the monocyte chemoattractant CCL2, were high in the myometrium, but also systemically in plasma and organ tissue, indicating a significant systemic inflammatory response. In the surgical controls, in which labour was delayed, there were substantial increases in Ly-6Chigh monocytes in the myometrium, which were shown using knockout mice to be CCR2-dependent. Taken together, our data indicate that both local and systemic inflammation play important roles in labour. Despite consistent observations of Ly-6Chigh monocyte infiltration into the myometrium, there was a lack of clear evidence supporting their role in labour, suggesting their late-gestation myometrium infiltration is more relevant to post-partum uterine repair and remodelling.
Supervisor: O'Dea, Kieran ; Johnson, Mark ; Takata, Masao Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral