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

Table 1 Pathophysiological mechanisms of hepatic ischemia-reperfusion injury

Mechanism	Description
Anaerobic metabolism	↓ ATP, intracellular metabolic acidosis, abnormal ion homeostasis
Calcium overload	↓ Intracellular calcium, activation of calcium-dependent enzymes, opening of MPTP, mediation of programmed cell death
Immune response	Kupffer cells activation, release of ROS and proinflammatory cytokines, infiltration of neutrophils and CD4+ T-lymphocytes
Kupffer cells activation	Release of ROS, TNF-α, IL-1β, IL-6, MCP-1, DAMPs, HMGB1, S100 proteins, heat shock proteins. Expression of ICAM-1, VCAM-1
Neutrophil activation	Release of ROS and MPO, production of elastase, cathepsin G, heparanase, collagenase and hydrolytic enzymes, NET formation
Oxidative stress	ROS production, damage of proteins and DNA, peroxidation of lipid membranes, activation of cell death pathways
Microcirculatory disturbance	Sinusoidal endothelial dysfunction, microvascular thrombosis
Mitochondrial dysfunction	Suppression of mitophagy, ROS production, ATP depletion, opening of MPTP, edema of mitochondria, rupture of mitochondrial membrane, damage of mtDNA, triggering of inflammatory response, activation of cell death pathways
Platelets accumulation	Microvascular embolism, release of serotonin, thromboxane A2, TGF-β, VEGF-A, PAI-1, enhancement of cytokine production
Complement activation	Promotion of neutrophil recruitment, Kupffer cells activation and cytokine release, direct hepatocytes and sinusoidal endothelial cells damage by MAC
miRNAs modulation	Post-transcriptional gene regulators, promotion of inflammatory response and programmed cell death, activation of NF-κB pathway
NO production	eNOS-derived NO improves hepatic microcirculation, promotes vasodilation, neutralizes ROS, inhibits platelet aggregation, limits leukocyte adhesion. iNOS-derived NO exacerbates hepatocellular injury, leads to excessive cytokine and ROS production. Lipid peroxidation, mitochondrial dysfunction
Cell death pathways	Necrosis, apoptosis, pyroptosis, ferroptosis, autophagy, NET-associated cell death, parthanatos, copper-induced and lysosome-dependent pathways

ATP: Adenosine triphosphate; MPTP: Mitochondrial permeability transition pore; ROS: Reactive oxygen species; TNF-α: Tumor necrosis factor α; IL-1β: Interleukin 1β; IL-6: Interleukin 6; MCP-1: Monocyte chemoattractant protein-1; DAMPs: Damage-associated molecular patterns; HMGB1: High mobility group box 1; ICAM-1: Intercellular adhesion molecule 1; VCAM-1: Vascular cell adhesion molecule 1; MPO: Myeloperoxidase; NET: Neutrophil extracellular trap; mtDNA: Mitochondrial DNA; TGF-β: Transforming growth factor-β; VEGF-A: Vascular endothelial growth factor A; PAI-1: Plasminogen activator inhibitor-1; MAC: Membrane attack complex; miRNAs: MicroRNAs; NF-κB: Nuclear factor kappa B; eNOS: Endothelial nitric oxide synthase; NO: Nitric oxide; iNOS: Inducible nitric oxide synthase.

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.

Table 3 Hepatic ischemia-reperfusion injury-associated remote organ damage

Organ	Underlying mechanisms	Mediators involved	Relative manifestations
Lungs	Systemic inflammatory response. Neutrophil and lymphocytes infiltration. Oxidative stress	TNF-α. ICAM-1. E-selectin. PAF. IL-6. IL-18. Substance P neutrophil-chemoattractant protein. ROS. WISP1	ALI. ARDS
Myocardium	Systemic inflammatory response. Oxidative stress. Hemodynamic instability	Cytokines. ROS. Adhesion molecules	Stress-induced cardiomyopathy postreperfusion syndrome. Arrhythmias
Kidney	Hemodynamic instability. Systemic inflammatory response. Oxidative stress. Renal endothelial and mitochondrial injury	ROS. PINK1. LC3. HIF-1. TNF-α. IL-6. IL-8. ET-1. IL-18. ICAM-1	AKI
Gastrointestinal system	Systemic inflammatory response. Oxidative stress. Postoperative liver failure	LPS. PRRs. TLR4. MAPK signaling pathway. NF-κB. Adhesion molecules	Mesenteric congestion increased intestinal permeability. Venous ischemia. Mucosal barrier disruption. Bacterial translocation
Pancreas	Oxidative stress increased apoptosis	lCAM-1. ROS	Pancreatic dysfunction. Acute pancreatitis
Brain	Increased BBB permeability. Infiltration of immune cells. Neuroinflammation. Neurodegeneration. Apoptosis	ROS. iNOS. TNF-α. IL-1β. IFN-γ. IL-6. Caspase-3. Bcl-2/Bax proteins ratio. NF-κB. Protein kinase 3	Cognitive impairment. Neuron injury

TNF-α: Tumor necrosis factor α; ICAM-1: Intercellular adhesion molecule 1; PAF: Platelet-activating factor; IL-6: Interleukin 6; IL-8: Interleukin 8; ROS: Reactive oxygen species; WISP1: WNT1-inducible signaling pathway protein 1; ALI: Acute lung injury; ARDS: Acute respiratory distress syndrome; PINK1: PTEN-induced kinase 1; LC3: Light chain 3; HIF-1: Hypoxia-inducible factor 1; ET-1: Endothelin-1; IL-18: Interleukin 18; AKI: Acute kidney injury; LPS: Lipopolysaccharide; PRRs: Pattern recognizing receptors; TLR4: Toll-like receptor 4; MAPK: Mitogen-activated protein kinase; NF-κB: Nuclear factor kappa B; BBB: Blood-brain barrier; iNOS: Inducible nitric oxide synthase; IL-1β: Interleukin 1β; IFN-γ: Interferon-γ.