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Title: The role of chemokines/chemokine receptors in labour
Author: Hua, Renyi
ISNI:       0000 0004 2728 9158
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2012
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Human labour is shown to be an inflammatory process, which involves a marked leukocyte infiltrate into myometrium during labour. My study focused on the role of chemokines, key mediators of leukocyte trafficking, in labour. Previous gene array data obtained from human labouring myometrium showed that the mRNA expression of the following chemokines was increased in term labouring myometrium, CCL2, CCL20, CXCL1, CXCL5, CXCL8. I decided to focus on myometrial expression of these chemokines and also to include CCL5, another important chemokine. My data confirmed that the expression of human myometrial chemokines was increased in labour and that their expression was up regulated by cytokines and mechanical stretch via NFKB and MAPK, but decreased by prostaglandins and oxytocin via PLC. I also studied the expression of myometrial chemokine receptors, which may mediate some of the effects of chemokines on myometrial function and/or act as decoys, minimising the effects of locally produced chemokines. I found that the expression of the chemokine receptors decreased with the onset of labour, mainly through the action of prostaglandins and oxytocin. I then used the established model of LPS-­‐induced preterm labour (PTL) in the mouse and found that chemokines and cytokines both increased in the myometrium and placenta. CCL2 is consistently increased with human labour and has been shown to be important in rodent parturition too. I therefore studied the impact of LPS in the CCR2 (the main receptor for CCL2) knockout mouse. There was less inflammation in both the myometrium and placenta and a better pup survival rate in the CCR2-/- mouse. However, the PTL was not delayed, suggesting that CCR2 is not essential for the induction of PTL labour by LPS in the mouse. I then turned my attention to CCL20, which acts only via CCR6. It is known to drive dendritic cell recruitment and I found that its expression was increased with labour, while that of its receptor was reduced. Functionally, I found that CCL20 up-regulated the myometrial expression of chemokines. Next I used the LPS-induced preterm labour model in the mouse and found that CCR6 knockout delayed LPS-induced preterm delivery and improved pup survival. These findings were associated with much lower inflammation in myometrium and plasma. These data suggest that CCR6 could be a therapeutic target in the management of PTL. Chemokines play an important role both in the induction of term labour and in infection induced PTL. Chemokine inhibitors may delay the onset of PTL and improve the fetal outcome.
Supervisor: Bennett, Phillip ; Sooranna, Dev ; Johnson, Mark Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral