title: Warm ischemia time-dependent variation in liver damage, inflammation, and function in hepatic ischemia/reperfusion injury.
abstract: Hepatic ischemia/reperfusion (I/R) injury is characterized by hepatocellular damage, sterile inflammation, and compromised postoperative liver function. Generally used mouse I/R models are too severe and poorly reflect the clinical injury profile. The aim was to establish a mouse I/R model with better translatability using hepatocellular injury, liver function, and innate immune parameters as endpoints.
  
  
  
  Mice (C57Bl/6J) were subjected to sham surgery, 30min, or 60min of partial hepatic ischemia. Liver function was measured after 24h using intravital microscopy and spectroscopy. Innate immune activity was assessed at 6 and 24h of reperfusion using mRNA and cytokine arrays. Liver inflammation and function were profiled in two patient cohorts subjected to I/R during liver resection to validate the preclinical results.
  
  
  
  In mice, plasma ALT levels and the degree of hepatic necrosis were strongly correlated. Liver function was bound by a narrow damage threshold and was severely impaired following 60min of ischemia. Severe ischemia (60min) evoked a neutrophil-dominant immune response, whereas mild ischemia (30min) triggered a monocyte-driven response. Clinical liver I/R did not compromise liver function and displayed a cytokine profile similar to the mild I/R injury model.
  
  
  
  Mouse models using ≤30min of ischemia best reflect the clinical liver I/R injury profile in terms of liver function dynamics and type of immune response.
  
  
  
  This short duration of ischemia therefore has most translational value and should be used to increase the prospects of developing effective interventions for hepatic I/R.
authors.affiliation: Department of Experimental Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Pim B
authors.initials: PB
authors.lastname: Olthof
authors.affiliation: Department of Experimental Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Rowan F
authors.initials: RF
authors.lastname: van Golen
authors.affiliation: Department of Cell Biology and Immunology, Wageningen University, Wageningen, The Netherlands.
authors.forename: Ben
authors.initials: B
authors.lastname: Meijer
authors.affiliation: Department of Cell Biology and Immunology, Wageningen University, Wageningen, The Netherlands.
authors.forename: Adriaan A
authors.initials: AA
authors.lastname: van Beek
authors.affiliation: Department of Nuclear Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Roelof J
authors.initials: RJ
authors.lastname: Bennink
authors.affiliation: Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Joanne
authors.initials: J
authors.lastname: Verheij
authors.affiliation: Department of Experimental Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: van Gulik
authors.affiliation: Department of Experimental Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. Electronic address: m.heger@amc.uva.nl.
authors.forename: Michal
authors.initials: M
authors.lastname: Heger
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D016207:Cytokines / Q000097:blood / Q000276:immunology; D004195:Disease Models, Animal; D006801:Humans; D007113:Immunity, Innate; D007249:Inflammation / Q000097:blood / Q000276:immunology / Q000473:pathology* / Q000503:physiopathology; D008099:Liver / Q000276:immunology / Q000473:pathology* / Q000503:physiopathology; D008297:Male; D008810:Mice, Inbred C57BL; D015427:Reperfusion Injury / Q000097:blood / Q000276:immunology / Q000473:pathology* / Q000503:physiopathology; D052096:Warm Ischemia / Q000379:methods*
chemical_list: D016207:Cytokines