TY - JOUR
T1 - Warm ischemia time-dependent variation in liver damage, inflammation, and function in hepatic ischemia/reperfusion injury
AU - Olthof, Pim B.
AU - van Golen, Rowan F.
AU - Meijer, Ben
AU - van Beek, Adriaan A.
AU - Bennink, Roelof J.
AU - Verheij, Joanne
AU - van Gulik, Thomas M.
AU - Heger, Michal
PY - 2017
Y1 - 2017
N2 - 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 last 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 capture 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
AB - 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 last 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 capture 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
U2 - https://doi.org/10.1016/j.bbadis.2016.10.022
DO - https://doi.org/10.1016/j.bbadis.2016.10.022
M3 - Article
C2 - 27989959
SN - 0925-4439
VL - 1863
SP - 375
EP - 385
JO - Biochimica et Biophysica Acta-Molecular Basis of Disease
JF - Biochimica et Biophysica Acta-Molecular Basis of Disease
IS - 2
ER -