PiggyBankKids

Dr David Maldonado-Perez

Brief project update from David

David looked at the potential role of lipoxin A4 during the labour of pregnancy. Lipoxin A4 is a compound present in all humans that has anti-inflammatory properties. It is widely known that inflammation is associated with infection or damage to a tissue. However, it is not so widely known that labour is also associated with an inflammatory response; inflammatory mediators are crucial for the initiation of labour. Although inflammation is required for labour to commence, the flip side of this is that premature and/or abnormal activation of the inflammatory response in the womb can lead to undesirable conditions such as premature labour or pre-eclampsia.
The objective of the present project is to investigate the use of lipoxin A4 in modulating the inflammatory response in the myometrium, the muscle component of the womb. So far my studies have identified the production of lipoxin A4 in the blood as well as in the myometrium of women during the third trimester of pregnancy. Lipoxin A4 works by binding to a receptor on the surface of cells. This receptor has also been identified in myometrium in pregnant women. Interestingly, the expression of the lipoxin receptor is increased during labour. We were able to reduce the amount of inflammation that was present in myometrial cells that we had cultured (ie grown in the laboratory) by adding lipoxin A4. These results suggest that lipoxin A4 plays an important role in dampening the inflammatory response once labour has commenced and they could potentially be used as therapeutic agents in the prevention of conditions such as premature labour.

I would like to take the opportunity to thank PiggyBankKids for supporting my research and to all the members of the Jennifer Brown Research Laboratory team.

Full report on David's project

During the last year David has focused on two main areas of research: Analysis of the role of anti inflammatory lipid mediators as modulators of inflammation during parturition. These results suggest that lipoxins may play an important role in parturition by modulating inflammatory events taking place in the myometrium and placenta during parturition. In addition, they suggest that administration of exogenous lipoxins as therapeutic agents could be a successful strategy in prevention of inappropriate preterm parturition that results from premature induction of the inflammatory response. Role of prostaglandins as modulators of the urokinase plasminogen activator (uPA) system during pregnancy.
Prostaglandins are lipid mediators that play crucial roles throughout pregnancy. During labour they are known to be involved in processes such as membrane rupture, cervical dilatation and myometrial contractility. However, the mechanisms by which these factors exert their actions in labour are not fully understood. This could explain the lack of success in the development of effective inhibitors that could prevent the actions of prostaglandins as a measure to suppress preterm labour or prolong pregnancy. It is essential to gain a better understanding of the mechanisms of action by which these factors exert their effects during labour.
David is exploring whether activation of prostaglandin receptors EP2 and FP expressed in the myometrium could play a role in the modulation of the plasminogen activator (uPA) system. The uPA system is central to a spectrum of biologic processes such as fibrinolysis, inflammation, matrix remodelling during wound healing, and angiogenesis (new blood vessel formation).

Research Grant Applications

An application to the Edinburgh Development Trust – Small Project Grants has been submitted in October 2009 to identify genes modulated by the anti-inflammatory mediator lipoxin A4 in pregnant myometrium by gene array analysis.

Publications

Maldonado-Pérez D, Golightly E, Denison FC, Jabbour HN, Norman JE. Role of Lipoxins as Modulators of Inflammation in Human Myometrium during Parturition. JCEM. Submitted.
Sales KJ, Grant V, Cook IH, Maldonado-Pérez D, Anderson RA, Williams ARW, Jabbour HJ. Interleukin-11 In Endometrial Adenocarcinoma Is Regulated By PGF2α-F-Prostanoid Receptor Interaction Via The Calcium- Calcineurin-NFAT Pathway And Negatively Regulated By The Regulator Of Calcineurin-1. Am J Pathol. Accepted.
Sales KJ, Maldonado-Pérez D, Grant V, Catalano RD, Wilson MR, Brown P, Williams ARW, Anderson RA, Jabbour HN.
Prostaglandin F2α-F-Prostanoid Receptor regulates CXCL8 expression in endometrial adenocarcinoma cells via The Calcium-Calcineurin-NFAT pathway.Biochim Biophys Acta. 2009 Oct 9. [Epub ahead of print].
Cook IH, Evans J, Maldonado-Pérez D, Critchley HO, Sales KJ, Jabbour HN. PROK1 modulates IL-11 expression via PROKR1 and the calcineurin/NFAT signalling pathway. Mol Hum Reprod. 2009 Oct 3. [Epub ahead of print].
Maldonado-Pérez D, Brown P, Morgan K, Millar RP, Thompson EA, Jabbour HN. Prokineticin 1 Modulates IL-8
Expression Via the Calcineurin/NFAT Signaling Pathway. Biochim Biophys Acta. 2009 Jul;1793(7):1315-24.
Maldonado-Perez, D., Denison, F.C., Jabbour, H.N. and Norman, J.E. (2009). Role of lipoxins as modulators of inflammation in human myometrium during parturition. Journal of Clinical Endocrinology and Metabolism. (in submission).
Amie J Moyes, David Maldonado-Perez, Gillian A Gray and Fiona C Denison. Enhanced angiogenic capacity of human umbilical vein endothelial cells from women with pre-eclampsia. Submitted to Placenta.

Presentations at Scientific Meetings
Maldonado-Pérez D, Golightly E, Roberts KA, Denison FC, Jabbour HN, Norman JE. Lipoxins – regulators of local inflammation in labor. Abstract submitted to the 2010 SGI 57th Annual Scientific Meeting, Orlando, U.S.A.
Maldonado-Pérez D, Roberts KA, Denison FC, Jabbour HN, Norman JE. Lipoxins – regulators of local inflammation in labour. Poster Presented at the Blair Bell Competition 2009, London, UK.
Maldonado-Perez D, Denison F, Norman JE, Jabbour HN. Role of Anti-Inflammatory / Pro-Resolution Lipid
Mediators during Labour. Poster Presented at 2009 SGI 56th Annual Scientific Meeting, Glasgow, UK.
Maldonado-Perez D, Wong R, Denison F, Norman JE, Jabbour HN. Modulation of the Urokinase-type Plasminogen Activator (uPA) System by Prostaglandins during Parturition. Oral presentation at the Blair Bell Competition 2008, Manchester, UK.
Maldonado-Perez D, Wong R, Denison F, Norman JE, Jabbour HN. Modulation of the Urokinase-type PlasminogenActivator (uPA) System by Prostaglandins during Parturition. Oral presentation at the Scottish Society for Experimental Medicine Meeting 2008, Edinburgh, UK.
David is hoping to complete his research during the coming year and is currently applying for admission to medical school as a graduate entrant.

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