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Defective monocyte oxidative burst predicts infection in alcoholic hepatitis and is associated with reduced expression of NADPH oxidase

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Title: Defective monocyte oxidative burst predicts infection in alcoholic hepatitis and is associated with reduced expression of NADPH oxidase
Authors: Vergis, N
Khamri, W
Beale, K
Sadiq, F
Aletrari, MO
Moore, C
Atkinson, SR
Bernsmeier, C
Possamai, L
Petts, G
Ryan, JM
Foxton, M
Hogan, B
Foster, GR
O'Brien, AJ
Ma, Y
Shawcross, D
Wendon, JA
Antoniades, CG
Thursz, MR
Item Type: Journal Article
Abstract: Objective In order to explain the increased susceptibility to serious infection in alcoholic hepatitis, we evaluated monocyte phagocytosis, aberrations of associated signalling pathways and their reversibility, and whether phagocytic defects could predict subsequent infection. Design Monocytes were identified from blood samples of 42 patients with severe alcoholic hepatitis using monoclonal antibody to CD14. Phagocytosis and monocyte oxidative burst (MOB) were measured ex vivo using flow cytometry, luminometry and bacterial killing assays. Defects were related to the subsequent development of infection. Intracellular signalling pathways were investigated using western blotting and PCR. Interferon-γ (IFN-γ) was evaluated for its therapeutic potential in reversing phagocytic defects. Paired longitudinal samples were used to evaluate the effect of in vivo prednisolone therapy. Results MOB, production of superoxide and bacterial killing in response to Escherichia coli were markedly impaired in patients with alcoholic hepatitis. Pretreatment MOB predicted development of infection within two weeks with sensitivity and specificity that were superior to available clinical markers. Accordingly, defective MOB was associated with death at 28 and 90 days. Expression of the gp91phox subunit of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase was reduced in patients with alcoholic hepatitis demonstrating defective MOB. Monocytes were refractory to IFN-γ stimulation and showed high levels of a negative regulator of cytokine signalling, suppressor of cytokine signalling-1. MOB was unaffected by 7 days in vivo prednisolone therapy. Conclusions Monocyte oxidative burst and bacterial killing is impaired in alcoholic hepatitis while bacterial uptake by phagocytosis is preserved. Defective MOB is associated with reduced expression of NADPH oxidase in these patients and predicts the development of infection and death.
Issue Date: 9-Feb-2016
Date of Acceptance: 25-Oct-2015
URI: http://hdl.handle.net/10044/1/27705
DOI: 10.1136/gutjnl-2015-310378
ISSN: 1468-3288
Publisher: BMJ Publishing Group
Start Page: 519
End Page: 529
Journal / Book Title: Gut
Volume: 66
Copyright Statement: © 2016 The Authors. This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/ licenses/by/4.0/
Sponsor/Funder: National Institute for Health Research
Rosetrees Trust
Medical Research Council (MRC)
Medical Research Council (MRC)
Funder's Grant Number: 08/14/44
JS16/M115-F1
MR/K010514/1
MR/M003132/1
Keywords: Science & Technology
Life Sciences & Biomedicine
Gastroenterology & Hepatology
CYTOKINE SIGNALING SOCS
ACUTE LIVER-FAILURE
INTERFERON-GAMMA
PULMONARY TUBERCULOSIS
VIRUS-INFECTION
UNITED-STATES
MACROPHAGES
CIRRHOSIS
DISEASE
SUPPRESSORS
ALCOHOLIC LIVER DISEASE
BACTERIAL INFECTION
IMMUNOLOGY IN HEPATOLOGY
1103 Clinical Sciences
1114 Paediatrics And Reproductive Medicine
Publication Status: Published
Appears in Collections:Division of Surgery
Faculty of Medicine



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