Brew, Obed ORCID: https://orcid.org/0000-0003-1710-6197 (2018) Placental genomics: regulatory roles of histamine in pre-eclampsia. Doctoral thesis, University of West London.

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Abstract

manifestation of PE in mothers who later develop the complication; histamine receptors H1 and H2, and DAO messages are expressed in juxtapositions at the foeto-maternal interface, Histidine Decarboxylase (HDC) HDC activity is elevated in PE placentae; and while elevated histamine upregulates the proteins for Th1-like cytokines, it also down-regulates DAO message expression after prolonged exposure in the placenta. The findings further show that lipopolysaccharides and pro-inflammatory cytokines including IL-10 and INF- increase histamine production in the placenta; and the histamine has a positive feedback loop regulatory relation with the proinflammatory cytokines. Furthermore, the validation of Elevated Histamine Model (EHM), an in vitro model designed for studying histamine effect in placenta showed that placental micro explants (∼50 mg) in long-term culture (explants that have undergone syncytiotrophoblast regeneration) at the liquid-gas interface in 8% oxygen is an optimum culture condition to study effects of histamine in the placenta. EHM produced RNA with quality akin to time zero pre-culture explants. The works also led to the identifications of a core set of significant genes that are consistently expressed in both normal (NP) in PE placentae but at varying levels, and a further subset of significant genes expressed consistently only in PE placentae (PE specific genes). Comparison of EHM significant genes with the PE specific genes confirmed the presence of 270 consistently expressed genes that appear to underpin the effects of elevated histamine in the placenta with implications for PE pathogenesis. Further analyses of these EHM genes in PE placentae showed that the natural process by which pre-eclampsia develops is affected by the amount of histamine in the maternal blood and placenta, and the natural process by which pre-eclampsia develops is indirectly affected by histamine via covariate functional groups regulated by specific histamine regulated PE placental genes. 5 Conclusion: Histamine receptor genes are expressed at the foeto-maternal interface; DAO genes are expressed in the placenta; HDC activity levels are increased in PE placentae; there is cross-talk between histamine, DAO and cytokines in the placenta; elevated histamine regulated the expression of specific genes in the placenta and these genes are abnormally expressed in PE placentae; the functions of the histamine regulated genes also identified in PE placentae are involved in tissue morphology and possibly poor placentation, metabolic defects, endothelial dysfunction, inflammation, immunologic response, angiogenic and anti-angiogenic response in PE placentae. Therefore it is reasonable to conclude that the elevated histamine observed in PE would have pathophysiological roles in PE and early detection leading to effective control of maternal blood histamine levels has survival values and it’s thus recommended.

Item Type:	Thesis (Doctoral)
Subjects:	Medicine and health
Depositing User:	Users 3908 not found.
Date Deposited:	31 Jul 2018 09:11
Last Modified:	04 Nov 2024 12:33
URI:	https://repository.uwl.ac.uk/id/eprint/5329

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