title: Immunosuppression in acutely decompensated cirrhosis is mediated by prostaglandin E2.
abstract: Liver disease is one of the leading causes of death worldwide. Patients with cirrhosis display an increased predisposition to and mortality from infection due to multimodal defects in the innate immune system; 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.
authors.affiliation: Centre for Clinical Pharmacology and Therapeutics, Division of Medicine, University College London, London, UK.
authors.forename: Alastair J
authors.initials: AJ
authors.lastname: O'Brien
authors.affiliation: Centre for Clinical Pharmacology and Therapeutics, Division of Medicine, University College London, London, UK.
authors.forename: James N
authors.initials: JN
authors.lastname: Fullerton
authors.affiliation: Manchester Pharmacy School, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK.
authors.forename: Karen A
authors.initials: KA
authors.lastname: Massey
authors.affiliation: Centre for Clinical Pharmacology and Therapeutics, Division of Medicine, University College London, London, UK.
authors.forename: Grace
authors.initials: G
authors.lastname: Auld
authors.affiliation: Division of Medicine, University College London, London, UK.
authors.forename: Gavin
authors.initials: G
authors.lastname: Sewell
authors.affiliation: Centre for Clinical Pharmacology and Therapeutics, Division of Medicine, University College London, London, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: James
authors.affiliation: Centre for Clinical Pharmacology and Therapeutics, Division of Medicine, University College London, London, UK.
authors.forename: Justine
authors.initials: J
authors.lastname: Newson
authors.affiliation: Centre for Clinical Pharmacology and Therapeutics, Division of Medicine, University College London, London, UK.
authors.forename: Effie
authors.initials: E
authors.lastname: Karra
authors.affiliation: Department of Histopathology, University College London Hospitals, London, UK.
authors.forename: Alison
authors.initials: A
authors.lastname: Winstanley
authors.affiliation: Liver Unit, Centre for Digestive Diseases, Blizard Institute of Cell and Molecular Science, Queen Mary University of London, London, UK.
authors.forename: William
authors.initials: W
authors.lastname: Alazawi
authors.affiliation: Hospital Clínic de Barcelona, Servicio de Hepatología, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Rita
authors.initials: R
authors.lastname: Garcia-Martinez
authors.affiliation: Centro de Investigacion Biomédica en Red de Enfermedades Hepaticas y Digestivas, Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Joan
authors.initials: J
authors.lastname: Cordoba
authors.affiliation: Manchester Pharmacy School, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK.
authors.forename: Anna
authors.initials: A
authors.lastname: Nicolaou
authors.affiliation: Centre for Clinical Pharmacology and Therapeutics, Division of Medicine, University College London, London, UK.
authors.forename: Derek W
authors.initials: DW
authors.lastname: Gilroy
mesh_terms: D000418:Albumins / Q000008:administration & dosage; D000818:Animals; D002251:Carbon Tetrachloride / Q000008:administration & dosage; D051546:Cyclooxygenase 2 / Q000097:blood; D016207:Cytokines / Q000378:metabolism; D015232:Dinoprostone / Q000096:biosynthesis / Q000097:blood* / Q000235:genetics; D005355:Fibrosis / Q000097:blood* / Q000276:immunology* / Q000473:pathology; D005786:Gene Expression Regulation; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects; D007113:Immunity, Innate; D007165:Immunosuppression Therapy; D008264:Macrophages / Q000201:enzymology; D051379:Mice; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000235:genetics* / Q000378:metabolism
chemical_list: D000418:Albumins; D016207:Cytokines; D058307:Receptors, Prostaglandin E, EP2 Subtype; D002251:Carbon Tetrachloride; D051546:Cyclooxygenase 2; D015232:Dinoprostone
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