Abu-alkheir, Wijdan Yahya; (2018) Novel Factors in Preeclampsia. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Preeclampsia (PE) is a hypertensive disorder of human pregnancy that is characterised by widespread vascular endothelial cell activation, inflammation, and oxidative stress. The regulation of chemokines and adhesion molecules in these cells is important in inflammatory responses. This thesis explores the hypothesis that the levels of soluble Fractalkine (sFkn), a marker of inflammation, are increased in PE, and that over-expression of the protective enzyme, heme oxygenase-1 (HO- 1), reduces sFkn. We found that sFkn release was not increased in plasma and placenta lysates in patients with PE compared to normal pregnancy. However, it was induced by the pro-inflammatory cytokines, tumour necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ), in human umbilical endothelial cells (HUVECs). Honokiol, an antioxidant agent, significantly reduced sFkn release. Collectively, these studies indicate that cytoprotective HO-1 pathway and Honokiol may offer partial protection against PE, by down-regulating sFkn and reducing the impact of pro-inflammatory factors in PE. Affymetrix Gene array profile of human placenta identified high expression of two new factors involved in the pathogenesis of PE, Noggin, and Leucine rich and immunoglobulin like domains protein 1 (Lrig1). This led us to investigate whether the expression level of Noggin and Lrig1 changes in preeclamptic placentas. Quantitative polymerase chain reaction (qPCR) revealed no significant differences in expression of Noggin at the messenger RNA (mRNA) level between normal and IV preeclamptic placenta. Western blot (WB) analysis of Noggin demonstrated an increase in the expression levels throughout gestation. In contrast, the expression of Lrig1, both at mRNA and at the protein level, was significantly higher in the PE placenta compared to the normal placenta. Immunohistochemical staining showed that Noggin and Lrig1 are expressed and localised in the cytotrophoblast and syncytiotrophoblast. These data suggest that Noggin and Lrig1 are found in human placenta and their expression is altered in PE. Further studies are needed to validate the significance of these early studies.

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