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Title: The role and regulation of oxytocin/oxytocin receptor system in human amnion and labour
Author: Kim, Sung Hye
ISNI:       0000 0004 5349 0445
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2014
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Preterm delivery occurs in 10% of all births. It is the major cause of infant death and handicap in the developed countries and accounts for 65% of neonatal deaths and 50% of childhood neurological disabilities. At the end of pregnancy, 'pro-labour' factors begin to mediate remodeling of the cervix resulting in cervical ripening and dilatation, uterine contractility and decidual/fetal membrane activation. The amnion plays an important role in the onset of human labour. It is a major site for prostaglandins (PG) and inflammatory cytokine synthesis which increases both before and during labour. Amnion derived inflammatory cytokines and prostaglandins contribute to the relaxation of the lower uterine segment and to cervical ripening. Oxytocin (OT) and oxytocin receptor (OTR) are classically considered to play a fundamental role in the mechanism of labour as OT stimulates uterine contractions and OTR antagonists are clinically used as tocolytics. The increase in OT and OTR expressions were observed in tissues other than myometrium, including the breast cells, decidua and amnion. However, amnion is not a contractile tissue and therefore the physiological role of the OT/OTR is less obvious. We hypothesised that the regulation of OT/OTR in human amnion is linked to NF-κB activity and plays an important role in the onset of labour. We have demonstrated that in human amnion, labour induces expression of both OT and OTR expression. Using specific inhibitors and siRNA target knockdown studies, we have shown that unlike the myometrial OTR, OT binding to OTR in human amnion drives the receptor to couple with Gαi2 and Gαi3, but not Gαq. This subsequently triggers the sequential activation of ERK, p38 MAPKs and NF-κB signalling cascades leading to PG and proinflammatory cytokine/chemokine synthesis. This suggests that OT not only induces uterine contractions but also plays a role in triggering the onset of labour by mediating the proinflammatory effects in the amnion. These proinflammatory effects of OT were suppressed by an OTR-specific antagonist, ornithine vasotocin (OVT), indicating that OT exerts its effects predominantly via OTR. However, the commonly used OTR antagonist, atosiban, had no effect on OT induced proinflammatory effects. Unexpectedly, atosiban treatment alone resulted in activation of inflammatory mediators such as MAPKs and NF-κB leading to downstream pro-labour gene expressions via Gαi. Activation of such inflammatory processes within the uterus initiates labor, whereas exposure to inflammation may be associated with fetal brain damage in preterm and term infants. Therefore, atosiban could exacerbate inflammation in the context of preterm birth and potentially have an effect on neonatal outcome. With this in mind the future development of OTR antagonists to prevent preterm birth will need to take into account the effects upon differential OTR G-protein coupling.
Supervisor: Terzidou, Vasso; Bennett, Phillip Sponsor: Action Medical Research ; National Institute for Health Research
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral