Bracken, Olivia Victoria; (2023) The effect of soluble epoxide hydrolase inhibition on the mononuclear phagocyte system during inflammation. Doctoral thesis (Ph.D), UCL (University College London).

Preview

Text Olivia Bracken_PhD thesis FINAL.pdf - Other Download (10MB) | Preview

Abstract

Evidence suggests a role for Cytochrome P450 metabolites, namely the epoxy-oxylipins, in facilitating the inflammatory response. The soluble epoxide hydrolase (sEH) enzyme metabolizes anti-inflammatory epoxy-oxylipins and I hypothesised that inhibition of this enzyme would transiently elevate levels of these lipids such that we can understand their role in inflammation and resolution. Therefore, healthy, male volunteers were challenged, intradermally, with UV-killed E. coli into each forearm. Participants in the drug arm were dosed with GSK2256294, a selective sEH inhibitor, orally 4 hours post bacterial injection. Peripheral blood and local inflammatory infiltrates were collected at 0, 4, 24 and 48 hours with the cell profiles analysed by polychromatic flow cytometry. Inhibiting sEH significantly elevated the levels of epoxy-oxylipins in plasma. In controls, numbers of Intermediate (CD14+CD16+) and Non-Classical (CD14-CD16+) monocytes in peripheral blood increased significantly between 4 and 24 hours following bacterial skin challenge. GSK2256294 prevented this increase. qPCR of PBMCs from participants shows a significant reduction in the levels of the p38 MAPK transcript in participants dosed with GSK2256294 and that epoxy-oxylipins prevent p38 phosphorylation in monocytes in vitro. Furthermore, I have shown in vitro that Losmapimod, a p38 MAPK inhibitor, prevents the expansion of intermediate and non-classical monocytes. This is the first study to demonstrate an sEH inhibitor-induced reduction in numbers of intermediate monocytes during experimental inflammation in humans and indicates that epoxy-oxylipins are one of the mechanistic drivers that control the monocyte differentiation pathway. I have shown that these lipids control the expression and phosphorylation of p38 MAPK, and that inhibition of this protein also prevents monocyte conversion, albeit in vitro. CD16+ monocytes are expanded and contribute to the pathogenesis of chronic inflammatory disease, and I hypothesise that treatment with GSK2256294 will reduce disease burden in these patients.

Download activity - last month

Export as CSVXMLJSON

Download activity - last 12 months

Export as XMLCSVJSON

Downloads by country - last 12 months

Export as JSONXMLCSV

Archive Staff Only

View Item