Parturition

Heads of Research Group:

• Professor Phillip Bennett
• Dr. Mark Sullivan
• Dr. Mark Johnson

Scientific staff:

• Dr. Yun Soo (Yooni) Lee
• Dr. Katie Groom
• Dr. Jenny Loudon (Action Research)
• Dr. Vasso Terzidou (WellBeing)
• Miss. Tamsin Lindström (WellBeing)
• Miss. Ruth Kirk (WellBeing)
• Mrs. Lyn Miles (Smith’s Charity)
• Dr Dev Soorana (Wellbeing)
• Dr. Louise Kim

The principal aims of the group:

"To investigate and identify the molecular mechanisms of human parturition"

Previous and current research:

1. Show that expression of COX-2, IL-1b and IL-8 increases before labour, and that this is linked to increased prostaglandin production from fetal membranes prior to labour.
2. Identify how the expression of these pro-labour genes is regulated, particularly through the transcription factor families of NFkB – IkB, and AP-1.
3. Investigate how a functional progesterone withdrawal at the end of human pregnancy could be mediated through (a) changes in progesterone receptors and (b) their interaction with other transcription factors.
4. Localise the pro-inflammatory pathways within human fetal, to identify which tissues and pathways are the primary functional targets for treatments for preterm labour.
5. Study the control of expression of the oxytocin receptor in myometrium, identifying the activating and suppressor pathways.
6. Determine whether potential tocolytics and NSAIDs have any effect on the contractility of human myometrium, and assess the mechanisms involved.
7. Investigate the breakdown of active prostaglandins by prostaglandin dehydrogenase (PGDH), and study how expression of PGDH is regulated.
8. Study the effects of stretch of myocytes upon expression of key labour associated genes
9. Undertake clinical studies of anti-inflammatory and other drugs which might help to prevent preterm delivery.

Plan of research for the near future:

The most important findings from our group in the last few years are that labour is associated with increased expression and activity of the type-2 cyclo-oxygenase gene and that the NF-kappa B transcription factor system regulates not only COX-2 but also the pro-inflammatory and pro-labour cytokine IL-8 and other labour associated proteins. We have also found that NF-kappa B is activated within the uterus and may interfere with the action of progesterone, to contribute to 'functional progesterone withdrawal'. Our clinical studies are concentrating upon identification of women at risk of preterm labour, using transvaginal ultrasound and on the role of cervical cerclage and COX-2 specific NSAI drugs in prevention of preterm labour. Our laboratory studies concentrate upon understanding how NF-kappa B is controlled within the uterus, what other genes it regulates, and the search for strategies to inhibit NF-kappa B and so switch off synthesis of a wider range of labour associated proteins. We also have a program to examine the effects of stretch upon the expression of labour associated proteins and to identify novel proteins implicated in the response of fetal membranes to intrauterine organisms.

Selected publications:

Brown NL, Alvi SA, Elder MG, Bennett PR & Sullivan MHF. A spontaneous induction of fetal membrane prostaglandin production precedes clinical labour. J. Endocrinol. 1998; 157: R1-R6.

Slater, D., Dennes, W., Sawdy, R., Allport, V. and Bennett, P. Expression of cyclo-oxygenase types-1 and -2 in human fetal membranes throughout pregnancy. J. Mol. Endocrinol. 1999; 22: 125-130.

Slater, D. M., Dennes, W. J., Campa, J. S., Poston, L. and Bennett, P. R. Expression of cyclo-oxygenase types-1 and -2 in human myometrium throughout pregnancy. Mol. Hum. Reprod. 1999; 5: 880-884

Brown NL, Alvi SA, Elder MG, Bennett PR and Sullivan MHF. The regulation of prostaglandin output from term intact fetal membranes by anti-inflammatory cytokines. Immunology 2000; 99: 124-133.

Sawdy, R. J., Slater, D. M., Dennes, W. J., Sullivan, M. H. and Bennett, P. R. The roles of the cyclo-oxygenases types one and two in prostaglandin synthesis in human fetal membranes at term. Placenta 2000; 21: 54-57.

Allport, V. C., Pieber, D., Slater, D. M., Newton, R., White, J. O. and Bennett, P. R. (2001). Human labour is associated with nuclear factor-kappaB activity which mediates cyclo-oxygenase-2 expression and is involved with the 'functional progesterone withdrawal'. Mol Hum. Reprod. 2001; 7: 581-586.

Elliott, C. L., Allport, V. C., Loudon, J. A., Wu, G. D. and Bennett, P. R. (2001) Nuclear factor-kappa B is essential for up-regulation of interleukin-8 expression in human amnion and cervical epithelial cells." Mol. Hum. Reprod. 2001; 7: 787-790.

Pieber, D., Allport, V. C., Hills, F., Johnson, M. and Bennett, P. R. Interactions between progesterone receptor isoforms in myometrial cells in human labour. Mol. Hum. Reprod. 2001; 7: 875-879.