title: CCL20 mediates lipopolysaccharide induced liver injury and is a potential driver of inflammation and fibrosis in alcoholic hepatitis.
abstract: OBJECTIVE
  Chemokines are known to play an important role in the pathophysiology of alcoholic hepatitis (AH), a form of acute-on-chronic liver injury frequently mediated by gut derived lipopolysaccharide (LPS). In our study, we hypothesise that chemokine CCL20, one of the most upregulated chemokines in patients with AH, is implicated in the pathogenesis of AH by mediating LPS induced liver injury.
  
  
  METHODS
  CCL20 gene expression and serum levels and their correlation with disease severity were assessed in patients with AH. Cellular sources of CCL20 and its biological effects were evaluated in vitro and in vivo in chronic, acute and acute-on-chronic experimental models of carbon tetrachloride and LPS induced liver injury. RNA interference technology was used to knockdown CCL20 in vivo.
  
  
  RESULTS
  CCL20 hepatic and serum levels were increased in patients with AH and correlated with the degree of fibrosis, portal hypertension, endotoxaemia, disease severity scores and short term mortality. Moreover, CCL20 expression was increased in animal models of liver injury and particularly under acute-on-chronic conditions. Macrophages and hepatic stellate cells (HSCs) were identified as the main CCL20 producing cell types. Silencing CCL20 in vivo reduced LPS induced aspartate aminotransferase and lactate dehydrogenase serum levels and hepatic proinflammatory and profibrogenic genes. CCL20 induced proinflammatory and profibrogenic effects in cultured primary HSCs.
  
  
  CONCLUSIONS
  Our results suggest that CCL20 upregulation is strongly associated with LPS and may not only represent a new potential biomarker to predict outcome in patients with AH but also an important mediator linking hepatic inflammation, injury and fibrosis in AH.
authors.affiliation: Liver Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Faculty of Medicine University of Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain.
authors.forename: Silvia
authors.initials: S
authors.lastname: Affò
authors.affiliation: Liver Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Faculty of Medicine University of Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain.
authors.forename: Oriol
authors.initials: O
authors.lastname: Morales-Ibanez
authors.affiliation: Liver Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Faculty of Medicine University of Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain.
authors.forename: Daniel
authors.initials: D
authors.lastname: Rodrigo-Torres
authors.affiliation: Liver Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Faculty of Medicine University of Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain.
authors.forename: José
authors.initials: J
authors.lastname: Altamirano
authors.affiliation: Liver Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Faculty of Medicine University of Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain.
authors.forename: Delia
authors.initials: D
authors.lastname: Blaya
authors.affiliation: Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York, USA.
authors.forename: Dianne H
authors.initials: DH
authors.lastname: Dapito
authors.affiliation: Liver Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Faculty of Medicine University of Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Millán
authors.affiliation: Liver Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Faculty of Medicine University of Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain.
authors.forename: Mar
authors.initials: M
authors.lastname: Coll
authors.affiliation: Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York, USA.
authors.forename: Jorge M
authors.initials: JM
authors.lastname: Caviglia
authors.affiliation: Liver Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Faculty of Medicine University of Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain.
authors.forename: Vicente
authors.initials: V
authors.lastname: Arroyo
authors.affiliation: Liver Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Faculty of Medicine University of Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Caballería
authors.affiliation: Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York, USA.
authors.forename: Robert F
authors.initials: RF
authors.lastname: Schwabe
authors.affiliation: Liver Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Faculty of Medicine University of Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain.
authors.forename: Pere
authors.initials: P
authors.lastname: Ginès
authors.affiliation: Liver Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Faculty of Medicine University of Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain Division of Gastroenterology and Hepatology, Departments of Medicine and Nutrition, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: Ramón
authors.initials: R
authors.lastname: Bataller
authors.affiliation: Liver Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Faculty of Medicine University of Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain.
authors.forename: Pau
authors.initials: P
authors.lastname: Sancho-Bru
mesh_terms: D065290:Acute-On-Chronic Liver Failure / Q000503:physiopathology*; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000503:physiopathology*; D054418:Chemokine CCL20 / Q000032:analysis / Q000097:blood / Q000502:physiology*; D005260:Female; D006519:Hepatitis, Alcoholic / Q000503:physiopathology*; D006801:Humans; D008070:Lipopolysaccharides / Q000009:adverse effects; D008297:Male; D051379:Mice; D008875:Middle Aged; D034741:RNA, Small Interfering; D015854:Up-Regulation / Q000502:physiology
chemical_list: D054418:Chemokine CCL20; D008070:Lipopolysaccharides; D034741:RNA, Small Interfering