Protective effect of ischemic preconditioning against hepatic ischemia-reperfusion injury and associated remote organ damage

Table 2 Protective pathways of ischemic preconditioning

Mechanism	Description
Improvement of hemodynamics	Enhancement of portal vein flow, improvement of micro-, macrovascular and sinusoidal perfusion
Modulation of inflammatory response	Reduction of Kupffer cells activation, attenuation of neutrophil recruitment, reduction in pro-inflammatory cytokine release, downregulation of CXC chemokine expression
Reduction of ROS production	Inhibition of XDH/XOD pathways, reduction of mitochondrial ROS production, inhibition of HMGB1 release, downregulation of NF-κB expression, reduction of TIM4 expression
Modulation of adenosine pathway	Enhancement of the adenosine generation, activation of adenosine A2 receptor-dependent pathways, modulation of endothelin, caspase inhibition, cytokine release downregulation, inhibition of adhesion molecule expression, suppression of neutrophil and platelet activity and reduction of ROS generation, activation of intracellular kinases
NO production	Promotion of eNOS-derived NO production, attenuation of hepatic sinusoidal vasoconstriction, reduction of inflammatory cell adhesion, suppression of pro-inflammatory transcription factor activation, regulation of programmed cell death
NO-associated prostaglandins production	Vasodilation, inhibition of inflammatory response, suppression of oxidative stress, inhibition of platelets aggregation
Regulation of calcium homeostasis	Prevention of intracellular calcium overload through adenosine pathway
Heat shock proteins	Preservation of mitochondrial integrity, repair of damaged proteins, protection against oxidative stress, suppression of proinflammatory cytokines and stabilization of the ion channels
NF-κB activation	Cyclin D1 transcription, promotion of hepatocyte proliferation
Modulation of miRNAs expression	Modulation of Jade1 protein expression, downregulation of mmu-miR-23a, mmu-miR-326, mmu-miR-346_MM1, and mmu-miR-370
Inhibition of programmed cell death pathways	Reduction of hepatocyte and sinusoidal endothelial cell apoptosis, preservation of mitochondrial function, prevention of necrosis

ROS: Reactive oxygen species; XDH: Xanthine dehydrogenase; XOD: Xanthine oxidase; HMGB1: High mobility group box 1; NF-κB: Nuclear factor kappa B; TIM4: T-cell immunoglobulin and mucin domain molecule-4; NO: Nitric oxide; eNOS: Endothelial nitric oxide synthase; miRNA: MicroRNAs.