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

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, 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.

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.

Conclusions: 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.

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.