title: Defective monocyte oxidative burst predicts infection in alcoholic hepatitis and is associated with reduced expression of NADPH oxidase.
abstract: 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.
  
  
  
  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.
  
  
  
  MOB, production of superoxide and bacterial killing in response toEscherichia coliwere 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 gp91phoxsubunit 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.
  
  
  
  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.
authors: Department of Hepatology and Gastroenterology, Imperial College, London, UK.
authors: Nikhil
authors: 0000-0002-4157-6757
authors: N
authors: Vergis
authors: Department of Hepatology and Gastroenterology, Imperial College, London, UK.
authors: Wafa
authors: W
authors: Khamri
authors: Department of Hepatology and Gastroenterology, Imperial College, London, UK.
authors: Kylie
authors: K
authors: Beale
authors: Department of Hepatology and Gastroenterology, Imperial College, London, UK.
authors: Fouzia
authors: F
authors: Sadiq
authors: Department of Hepatology and Gastroenterology, Imperial College, London, UK.
authors: Mina O
authors: MO
authors: Aletrari
authors: Department of Hepatology and Gastroenterology, Imperial College, London, UK.
authors: Celia
authors: C
authors: Moore
authors: Department of Hepatology and Gastroenterology, Imperial College, London, UK.
authors: Stephen R
authors: SR
authors: Atkinson
authors: Department of Hepatology, King's College Hospital, Institute of Liver Studies, London, UK.
authors: Christine
authors: C
authors: Bernsmeier
authors: Department of Hepatology and Gastroenterology, Imperial College, London, UK.
authors: Lucia A
authors: LA
authors: Possamai
authors: Department of Hepatology and Gastroenterology, Imperial College, London, UK.
authors: Gemma
authors: G
authors: Petts
authors: Department of Hepatology, King's College Hospital, Institute of Liver Studies, London, UK.
authors: Jennifer M
authors: JM
authors: Ryan
authors: Department of Hepatology, King's College Hospital, Institute of Liver Studies, London, UK.
authors: Robin D
authors: RD
authors: Abeles
authors: Department of Hepatology, University College, London, UK.
authors: Sarah
authors: S
authors: James
authors: Chelsea and Westminster Hospital, London, UK.
authors: Matthew
authors: M
authors: Foxton
authors: Department of Hepatology, Royal Free Hospital, London, UK.
authors: Brian
authors: B
authors: Hogan
authors: Department of Gastroenterology, Royal London Hospital, London, UK.
authors: Graham R
authors: GR
authors: Foster
authors: Department of Hepatology, University College, London, UK.
authors: Alastair J
authors: AJ
authors: O'Brien
authors: Department of Hepatology, King's College Hospital, Institute of Liver Studies, London, UK.
authors: Yun
authors: Y
authors: Ma
authors: Department of Hepatology, King's College Hospital, Institute of Liver Studies, London, UK.
authors: Debbie L
authors: DL
authors: Shawcross
authors: Department of Hepatology, King's College Hospital, Institute of Liver Studies, London, UK.
authors: Julia A
authors: JA
authors: Wendon
authors: Department of Hepatology and Gastroenterology, Imperial College, London, UK.
authors: Charalambos G
authors: CG
authors: Antoniades
authors: Department of Hepatology and Gastroenterology, Imperial College, London, UK.
authors: Mark R
authors: MR
authors: Thursz
mesh_terms: D000328:Adult; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D001424:Bacterial Infections / Q000276:immunology*; D016022:Case-Control Studies; D002478:Cells, Cultured; D018920:Coculture Techniques; D015169:Colony Count, Microbial; D004926:Escherichia coli / Q000276:immunology; D005260:Female; D006519:Hepatitis, Alcoholic / Q000188:drug therapy / Q000201:enzymology / Q000503:physiopathology*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D008875:Middle Aged; D009000:Monocytes / Q000502:physiology*; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000378:metabolism*; D010587:Phagocytosis; D011237:Predictive Value of Tests; D011239:Prednisolone / Q000627:therapeutic use; D016897:Respiratory Burst / Q000187:drug effects; D015398:Signal Transduction; D000071222:Suppressor of Cytokine Signaling 1 Protein / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D008562:Membrane Glycoproteins; C108944:SOCS1 protein, human; D000071222:Suppressor of Cytokine Signaling 1 Protein; D007371:Interferon-gamma; D011239:Prednisolone; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases
keywords: ALCOHOLIC LIVER DISEASE; BACTERIAL INFECTION; IMMUNOLOGY IN HEPATOLOGY