title: Clinical relevance and cellular source of elevated soluble urokinase plasminogen activator receptor (suPAR) in acute liver failure.
abstract: OBJECTIVE
  Acute liver failure (ALF) is a life-threatening condition with a high mortality rate. The expression of urokinase plasminogen activator receptor (uPAR, CD87) and release of its shedded receptor into serum as soluble uPAR (suPAR) have been closely related to immune activation and prognosis in systemic inflammation and cirrhosis. We now aimed at investigating the clinical relevance and cellular source of uPAR and circulating suPAR in ALF.
  
  
  METHODS
  Serum suPAR concentrations were measured in 48 ALF patients and 62 healthy controls from a German liver transplantation centre. Hepatic immune cell subsets and uPAR expression were studied by FACS, qPCR and immunohistochemistry.
  
  
  RESULTS
  Circulating suPAR levels were significantly increased in ALF patients, independent from the underlying aetiology, in comparison to controls. Serum suPAR concentrations were closely correlated with parameters reflecting liver cell injury, decreased liver function and the model of end-stage liver disease (MELD) score in ALF patients. By immunohistochemistry from explanted livers, ALF was associated with distinct immune cell accumulation and strong up-regulation of intrahepatic uPAR mRNA expression. CD87 (uPAR) expression was specifically detected on intrahepatic 'non-classical' monocytes (CD14(+) CD16(+) ), NKT and CD56(dim) NK cells isolated from human liver, but not on parenchymal or other non-parenchymal hepatic cell types. Membrane-bound uPAR was rapidly cleaved from monocytes upon inflammatory stimulation by lipopolysaccharide (LPS) and partially by co-cultured lymphocytes.
  
  
  CONCLUSIONS
  Similar to its prognostic properties in patients with sepsis or cirrhosis, intrahepatic uPAR activation and serum suPAR concentrations might serve as an interesting biomarker in ALF.
authors.affiliation: Department of Medicine III, RWTH-University Hospital Aachen, Aachen, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Koch
authors.forename: Henning W
authors.initials: HW
authors.lastname: Zimmermann
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Gassler
authors.forename: Christoph
authors.initials: C
authors.lastname: Jochum
authors.forename: Ralf
authors.initials: R
authors.lastname: Weiskirchen
authors.forename: Jan
authors.initials: J
authors.lastname: Bruensing
authors.forename: Lukas
authors.initials: L
authors.lastname: Buendgens
authors.forename: Hanna
authors.initials: H
authors.lastname: Dückers
authors.forename: Tony
authors.initials: T
authors.lastname: Bruns
authors.forename: Guido
authors.initials: G
authors.lastname: Gerken
authors.forename: Ulf P
authors.initials: UP
authors.lastname: Neumann
authors.forename: David H
authors.initials: DH
authors.lastname: Adams
authors.forename: Christian
authors.initials: C
authors.lastname: Trautwein
authors.forename: Ali
authors.initials: A
authors.lastname: Canbay
authors.forename: Frank
authors.initials: F
authors.lastname: Tacke
mesh_terms: D015415:Biomarkers / Q000097:blood*; D005434:Flow Cytometry; D005858:Germany; D006801:Humans; D007150:Immunohistochemistry; D007694:Killer Cells, Natural / Q000276:immunology; D008099:Liver / Q000276:immunology*; D017114:Liver Failure, Acute / Q000097:blood* / Q000276:immunology*; D009000:Monocytes / Q000276:immunology; D016133:Polymerase Chain Reaction; D055293:Receptors, Urokinase Plasminogen Activator / Q000097:blood*
chemical_list: D015415:Biomarkers; C524898:PLAUR protein, human; D055293:Receptors, Urokinase Plasminogen Activator
keywords: CD87; acute liver failure; monocytes; organ failure; prognosis; suPAR