UCL Discovery
UCL home » Library Services » Electronic resources » UCL Discovery

Immunosuppression in acutely decompensated cirrhosis is mediated by prostaglandin E-2

O'Brien, AJ; Fullerton, JN; Massey, KA; Auld, G; Sewell, G; James, S; Newson, J; ... Gilroy, DW; + view all (2014) Immunosuppression in acutely decompensated cirrhosis is mediated by prostaglandin E-2. Nature Medicine , 20 (5) pp. 518-523. 10.1038/nm.3516. Green open access

[thumbnail of O'Brien_Combine.pdf]
Preview
Text
O'Brien_Combine.pdf - Accepted version

Download (7MB) | Preview

Abstract

Liver disease is one of the leading causes of death worldwide1. Patients with cirrhosis display an increased predisposition to and mortality from infection due to multimodal defects in the innate immune system2,3,4; however, the causative mechanism has remained elusive. We present evidence that the cyclooxygenase (COX)-derived eicosanoid prostaglandin E2 (PGE2) drives cirrhosis-associated immunosuppression. We observed elevated circulating concentrations (more than seven times as high as in healthy volunteers) of PGE2 in patients with acute decompensation of cirrhosis. Plasma from these and patients with end-stage liver disease (ESLD) suppressed macrophage proinflammatory cytokine secretion and bacterial killing in vitro in a PGE2-dependent manner via the prostanoid type E receptor-2 (EP2), effects not seen with plasma from patients with stable cirrhosis (Child-Pugh score grade A). Albumin, which reduces PGE2 bioavailability, was decreased in the serum of patients with acute decompensation or ESLD (<30 mg/dl) and appears to have a role in modulating PGE2-mediated immune dysfunction. In vivo administration of human albumin solution to these patients significantly improved the plasma-induced impairment of macrophage proinflammatory cytokine production in vitro. Two mouse models of liver injury (bile duct ligation and carbon tetrachloride) also exhibited elevated PGE2, reduced circulating albumin concentrations and EP2-mediated immunosuppression. Treatment with COX inhibitors or albumin restored immune competence and survival following infection with group B Streptococcus. Taken together, human albumin solution infusions may be used to reduce circulating PGE2 levels, attenuating immune suppression and reducing the risk of infection in patients with acutely decompensated cirrhosis or ESLD.

Type: Article
Title: Immunosuppression in acutely decompensated cirrhosis is mediated by prostaglandin E-2
Open access status: An open access version is available from UCL Discovery
DOI: 10.1038/nm.3516
Publisher version: https://doi.org/10.1038/nm.3516
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Science & Technology, Life Sciences & Biomedicine, Biochemistry & Molecular Biology, Cell Biology, Medicine, Research & Experimental, Research & Experimental Medicine, CHRONIC LIVER-FAILURE, INFECTIONS, MACROPHAGE, PHAGOCYTOSIS, INFLAMMATION, DYSFUNCTION, PREVALENCE, SUPPRESSES, MANAGEMENT, HEPATITIS
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 Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy
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
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Inst for Liver and Digestive Hlth
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Inst of Clinical Trials and Methodology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Inst of Clinical Trials and Methodology > Comprehensive CTU at UCL
URI: https://discovery.ucl.ac.uk/id/eprint/10055885
Downloads since deposit
97Downloads
Download activity - last month
Download activity - last 12 months
Downloads by country - last 12 months

Archive Staff Only

View Item View Item