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.