Warm ischemia time-dependent variation in liver damage, inflammation, and function in hepatic ischemia/reperfusion injury

Pim B. Olthof, Rowan F. van Golen, Ben Meijer, Adriaan A. van Beek, Roelof J. Bennink, Joanne Verheij, Thomas M. van Gulik, Michal Heger*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

23 Citations (Scopus)

Abstract

Background 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. Methods Mice (C57Bl/6J) were subjected to sham surgery, 30 min, or 60 min of partial hepatic ischemia. Liver function was measured after 24 h using intravital microscopy and spectroscopy. Innate immune activity was assessed at 6 and 24 h 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. 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 60 min of ischemia. Severe ischemia (60 min) evoked a neutrophil-dominant immune response, whereas mild ischemia (30 min) 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. Conclusions Mouse models using ≤ 30 min of ischemia best reflect the clinical liver I/R injury profile in terms of liver function dynamics and type of immune response. General significance 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.

Original languageEnglish
Pages (from-to)375-385
JournalBiochimica et Biophysica Acta. Molecular Basis of Disease
Volume1863
Issue number2
DOIs
Publication statusPublished - 2017

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