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The effect of soluble epoxide hydrolase inhibition on the mononuclear phagocyte system during inflammation

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). Green open access

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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.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: The effect of soluble epoxide hydrolase inhibition on the mononuclear phagocyte system during inflammation
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Copyright © The Author 2022. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request.
Keywords: Epoxy-oxylipins, Human, Inflammation, Monocytes
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Experimental and Translational Medicine
URI: https://discovery.ucl.ac.uk/id/eprint/10165135
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