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The Role of Prostaglandin E2 in Innate Immune Dysfunction in Cirrhotic Liver Disease

Maini, Alexander Amar Nath; (2018) The Role of Prostaglandin E2 in Innate Immune Dysfunction in Cirrhotic Liver Disease. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Liver cirrhosis is one of the greatest causes of mortality in the world in the 21st century. The prevalence of liver disease is predicted to continue to rise precipitously and liver disease accounts for between 2% and 3% of annual worldwide deaths. Bacterial infection is the major cause of mortality in liver cirrhosis and these patients are highly prone to nosocomial infection. Innate immune dysfunction is strongly implicated in this process. O’Brien et al (Nature Med, 2014) showed prostaglandin E2 (PGE2) was markedly increased in these patients. However, traditional approaches to reducing PGE2 (such as NSAIDs) are contraindicated due to renal and gastrointestinal side effects. This study aimed to investigate PGE2 downstream signalling pathways to identify a more specific druggable target to reverse immune dysfunction in acute-on-chronic liver failure (ACLF) and cirrhotic patients in general. ACLF patients (mean modified End-Stage Liver Disease (MELD) score 19) were compared to outpatients with resistant ascites admitted for elective paracentesis and drainage, ‘ambulant’, cirrhotic patients and healthy volunteers (HV). PGE2 levels in plasma were significantly increased between HV (163.9pg/ml) and ACLF (563.8pg/ml). I demonstrated increased microsomal Prostaglandin-E-Synthase-1 expression in cirrhotic liver parenchyma and increased phospholipase A2 expression and cyclooxygenase (COX)-2:COX-1 expression ratio in monocytes. ACLF and ambulant patients had increased circulating cytokines, including IL-6, IL-8, and TNF-a, as well as demonstrating a monocyte phenotype of immune fatigue, with low HLA-DR. Ex vivo lipopolysaccharide (LPS)-whole blood stimulation demonstrated monocyte deactivation with significantly lower levels of TNF-a and IL-6 in ACLF vs HV (2.178ng/109monocytes vs 6.649ng/109monocytes and 4.492ng/109monocytes vs 12.256ng/109monocytes respectively). This was further reduced by addition of exogenous PGE2 at inflammatory site concentrations. PGE2 acts through four membrane-bound G protein-coupled receptors with different activities, EP1-4. Blockade of the EP4 receptor completely reversed reduction in both TNF-a and IL-6. Similar changes were seen locally using an in vivo model of inflammation, including increased PGE2 concentrations at a local inflammatory site. In summary, ACLF patients have PGE2-mediated monocyte deactivation via the EP4 receptor. Blockade of this receptor restored innate immune function. EP4 blockade has been shown to have a safe renal profile and I suggest this is a valid target for future immune-restorative therapy in ACLF.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: The Role of Prostaglandin E2 in Innate Immune Dysfunction in Cirrhotic Liver Disease
Event: UCL (University College London)
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Copyright © The Author 2018. Original content in this thesis is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/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.
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
URI: https://discovery.ucl.ac.uk/id/eprint/10061904
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