Introduction

Ischemia-reperfusion injury (IRI) is characterized by initial organ underperfusion (ischemia), followed by restoration of blood flow (reperfusion) [1]. Although restoration of oxygen delivery to an ischemic organ is needed to prevent hypoxic cellular damage, reperfusion may accentuate organ injury in excess of the stress produced by ischemia itself [1]. IRI can occur in diverse clinical settings including organ transplantation, trauma, shock, cardiopulmonary bypass, and thrombolytic therapy. Hepatic IRI is a major complication of hepatic resection surgery (e.g., the Pringle maneuver) and liver transplantation. This pathological condition can lead to liver cellular damage and clinical hepatic dysfunction, and may even predispose to distant organ failure.

Pathophysiology

Various pathophysiological mechanisms have been proposed for hepatic IRI, but the actual mechanisms remain unclear. Hepatic IRI occurs in two main settings. First, ischemia can follow temporary vascular occlusion of the hepatic pedicle or various forms of shock and trauma, whereby hypoxic injury occurs. Second, reperfusion injury can be added to hepatic ischemic injury. This phenomenon is a dynamic process that leads to metabolic acidosis, intracellular calcium overload, mitochondrial damage, Kupffer cell activation, oxidative stress, inflammatory responses, and necrotic or apoptotic cell death (Fig. 1) [2].

1. Metabolic acidosis

Metabolic acidosis is the basic mechanism underlying hepatic IRI [3]. It results from anaerobic glycolysis during ischemia, which leads to depletion of adenosine 5′-triphosphate (ATP) from organs, consequently producing lactate. During reperfusion, the tissue pH increases, leading to the activation of phospholipases and proteolytic enzymes, which in turn cause cell damage, necrosis, and apoptosis, resulting in IRI [3].

2. Intracellular calcium overload

Intracellular calcium homeostasis is maintained by the Na⁺/K⁺ and H⁺/Ca²⁺ exchange systems. During ischemia and reperfusion, ATP depletion leads to a decrease in ATP-dependent Na⁺/K⁺ ATPase activity in the cell membrane. This results in increased intracellular Na⁺ concentrations, leading to the inward flux of calcium ions [4]. In addition, increased ischemia-induced permeability of cell membranes causes further movement of calcium ions into the cell, and a large number of calcium ions are released from the endoplasmic reticulum and damaged mitochondria. Intracellular calcium overload occurs, which in turn interferes with cellular metabolic pathways [5].

3. Mitochondrial damage

Mitochondria act as pathological triggers, mediators, and effectors of hepatic IRI [6]. Mitochondrial functions normally involve several processes, including energy production, cell survival, and programmed cell death [7]. However, the dysfunction in pathological ischemia and reperfusion is initiated by mitochondrial permeability transition (MPT) pore opening [8]. ATP depletion, calcium ion overload, and toxic oxidant release promote MPT onset, which follows depolarization of the mitochondrial membrane potential, matrix swelling, and membrane rupture [9]. Moreover, MPT opening can lead to apoptosis by mitochondrial swelling and the subsequent release of cytochrome C [10].

4. Oxidative stress

1) Reactive oxygen species

Reactive oxygen species (ROS) normally exist as by-products of cellular metabolism in proteins, lipids, nucleic acids, and other biologically active molecules. However, the nature and amount of ROS change during IRI. Aerobic cells use molecular oxygen to remove electrons during oxidative catabolism (from O₂ to H₂O) in the mitochondrial respiratory chain. However, small amounts of oxygen (1%–3%) are reduced through the univalent pathway, forming reactive intermediate species, including superoxide anion (O₂^•–), hydrogen peroxide (H₂O₂), and hydroxyl radical (^•HO) [11,12]. Metal ions such as iron and copper react with hydrogen peroxide via the Fenton reaction, producing the toxic hydroxyl radical [13]. Superoxide anion and these reactive intermediates are known as ROS [12].

Many metabolic processes, including the enzymatic activities of xanthine oxidase (XO) and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, for example, and mitochondrial respiration produce large amounts of ROS [14]. Although XO is known to be an important mediator of ROS formation, mitochondria have recently been suggested as the main production site for large amounts of superoxide, leading to the formation of MPT pores that can cause cell death [15].

2) Reactive nitrogen species

Nitric oxide (NO), nitrogen dioxide, and peroxynitrite (ONOO^–) are biologically important reactive nitrogen species (RNS), the last two of which result from the interaction of NO with molecular oxygen [16]. Among these, ONOO^–, a strong oxidizing agent generated from superoxide anion and NO, can attack basic cell constituents, such as DNA and proteins [17]. NO, a gaseous signaling molecule is produced by the enzymatically catalyzed reaction between L-arginine and oxygen [18]. During hepatic IRI, two main NO synthases (NOS), endothelial (eNOS) and inducible (iNOS), synthesize NO, which can either prevent or promote cell injury [19]. eNOS is constitutively expressed in sinusoidal endothelial cells, whereas iNOS is stimulated by numerous cytokines, such as tumor necrosis factor alpha (TNF-α) and interleukin-1 (IL-1) [19]. NO exerts a protective effect on parenchymal hepatocytes by preventing the action of TNF-α and apoptotic factors, blocking MPT onset, and preventing sinusoidal obstruction by inducing vasodilatation, neutrophil accumulation, and platelet adhesion [20-22]. However, overproduction of NO during the late reperfusion period can result in high levels of injurious ROS and the accumulation of inflammatory cytokines by increased iNOS expression and decreased eNOS expression [18]. In addition, NO can be converted into the toxic ONOO^–, which can cause tissue injury through multiple pathways, including lipid peroxidation, inhibition of the mitochondrial respiratory chain, and modification of protein nitrotyrosine levels [23-25]. Thus, NO can promote or prevent cell survival, depending on its concentration, activation time, and NO-superoxide radical ratio.

Therefore, ROS and RNS directly react with numerous biological molecules, leading to tissue toxicity. The above effects damage sinusoidal endothelial cells, increasing permeability of the microvasculature and promoting neutrophil and platelet adhesion to these cells, followed by subsequent disruption of the microcirculation [26]. Moreover, these oxygen radicals lead to hepatocellular apoptosis by influencing intracellular signaling pathways via effects on gene expression and direct oxidation of nuclear DNA structure in the hepatic parenchyma [27].

3) Antioxidant systems

In contrast to the generation of ROS and RNS, the presence of endogenous antioxidant enzymes attenuates further hepatic injury. When present at low concentrations, antioxidant enzymes can prevent oxidative damage and detoxify ROS [28]. Hepatocytes contain high levels of intracellular antioxidant enzymes, including superoxide dismutase (SOD), glutathione peroxidase, and catalase; however, during IRI, an imbalance between ROS and endogenous antioxidant enzymes occurs, consequently leading to damage to nucleic acids, proteins, and lipids [27]. SOD catalyzes the dismutation of superoxide anion to hydrogen peroxide and oxygen [27]. Hydrogen peroxide can be decomposed via three main systems. First, catalase breaks down hydrogen peroxide into oxygen and water [27]. Second, glutathione peroxidase removes hydrogen peroxide via glutathione oxidation to glutathione disulfide [27]. Finally, peroxiredoxins reduce hydrogen peroxide to water [29].

5. Inflammatory responses

1) Inflammatory cells

Hepatic IRI is characterized by inflammatory responses in the postischemic tissue. During ischemia, a lack of ATP causes failure of the Na⁺/K⁺ ATPase and subsequent intracellular Na⁺ accumulation with cellular swelling in hepatocytes, Kupffer cells, and sinusoidal endothelial cells. Here, increased endothelin and decreased NO (a vasoconstrictor and vasodilator, respectively) levels induce cellular swelling, which in turn leads to sinusoidal narrowing [30]. During reperfusion, the attachment of neutrophils and platelets to the sinusoid with increased adhesion molecules leads to defects in hepatic microcirculation and even the complete absence of blood flow and reflow [26].

Kupffer cells, the resident hepatic macrophages, play a pivotal role in initiating hepatic cellular damage in IRI [31]. During ischemia and the early reperfusion period, Kupffer cells release proinflammatory mediators, such as TNF-α, IL-1, platelet-activating factor, and ROS, which activate a cascade of inflammatory responses [32]. These inflammatory cytokines, chemokines, and small molecule mediators recruit neutrophils and induce ROS production and further inflammation, exacerbating tissue damage during the late reperfusion period [33]. In addition, Kupffer cells activate CD4⁺ T lymphocytes in the early reperfusion period, preceding neutrophil accumulation induced by the chemotactic agent IL-17. Reciprocally, CD4⁺ T cells release interferon-gamma, which activates Kupffer cells to generate TNF-α and IL-1 [34,35]. Over a time scale similar to that of the CD4⁺ T cells, natural killer cells, another leukocyte subset, are recruited to the liver; they produce interferon-gamma, aggravating IRI [36].

2) Complement and cytokines

The complement system and cytokines are important humoral factors involved in hepatic IRI. Once activated in IRI, complement can damage either directly by lysing hepatocytes through the membrane attack complex or indirectly by activating Kupffer cells and neutrophils [26]. Among the complement components, C5a is the most potent inflammatory mediator that releases proinflammatory cytokines, including TNF-α, IL-1, and IL-6 [37]. In addition, C5a inhibits endothelium-dependent relaxation and alters vascular tone, which further compromises the blood flow to ischemic tissues [37].

Numerous cytokines can play one of two roles, either proinflammatory or anti-inflammatory. TNF-α is a crucial proinflammatory cytokine in the hepatic inflammatory response during ischemia and reperfusion. Although various cells in the liver release TNF-α, its production by Kupffer cells is the most prominent [38]. Upregulation of TNF-α during ischemia and reperfusion results in ROS activation, expression of various adhesion molecules such as intercellular adhesion molecule 1 and P-selectin, and thus recruitment of neutrophils into the liver [39]. Similarly, IL-1 can induce ROS production and promote leukocyte aggregation [40]. Conversely, IL-6 produced by Kupffer cells has a protective effect that is mediated by the downregulation of oxidative stress markers and increase in glutathione, an antioxidant, thus reducing hepatocyte damage [41].

3) Endogenous danger signals

One question that arises is how immune cells are stimulated by pathogens in surgical settings. The answer begins with hepatic oxidative stress. During ischemia and reperfusion, ROS and RNS generated by mitochondrial respiration threaten hepatocyte viability [42]. Damaged hepatocytes and other immune cells (e.g., Kupffer cells and neutrophils) release pathogenic endogenous molecules and danger-associated molecular patterns (DAMPs) that overactivate innate immune responses [43]. DAMPs and self-antigens are normally physiological constituents of healthy cells; however, they become immunostimulators in the extracellular environment. Consequently, DAMPs stimulate Kupffer cells, which results in the production of inflammatory mediators, such as cytokines, chemokines, and ROS. This process induces reperfusion injury via intense neutrophil infiltration [32]. In other words, oxygen-free radicals and proinflammatory cytokines released by activated Kupffer cells can promote the infiltration of neutrophils and platelets into sinusoidal endothelium, thereby disrupting hepatic microcirculation and further aggravating hepatic injury [44]. Among the various DAMPs in hepatic IRI, high-mobility group box-1 is the best characterized. It is released by damaged hepatocytes and interacts with toll-like receptors (TLRs), particularly TLR-4 [45]. In this instance, several signaling transcription factors mediate TLR-4 activation, including nuclear factor-kappa B, activating protein-1, and mitogen-activated protein kinases (ERK, JNK, and P38), which modulate gene expression correlated with inflammatory progression [45,46]. Thus, DAMP-derived danger signals mediate the contribution of leukocytes to the severity of liver damage-induced ischemia and reperfusion.

Protective strategies for hepatic ischemia-reperfusion injury

1. Modulation of oxidative stress

Oxidative stress occurs when oxidants are overproduced or antioxidant levels are reduced. Therefore, treatment strategies for oxidant modulation include the inhibition of ROS formation, scavenging of ROS, and potentiation of endogenous antioxidant capacity. As mentioned above, XO, NADPH oxidase, and MPT collectively contribute to ROS formation. Many studies have demonstrated the protective effects of inhibition of these enzymes in hepatic IRI. For example, known inhibitors are allopurinol [47] and apocynin [48] for XO and NADPH oxidase, respectively. Additionally, edaravone, a mitochondria-specific antioxidant with protective effects against hepatic IRI, has been experimentally confirmed as an MPT inhibitor. It exerts its effect by blocking the MPT and maintaining an adequate ATP concentration [49]. Moreover, cyclosporin A inhibits MPT pore opening in the mitochondrial matrix; however, its clinical use remains limited [50].

Normally, the antioxidant defense system controls ROS production. Various antioxidant defenses have been demonstrated to have beneficial effects, both experimentally and clinically, in hepatic IRI. Antioxidants are a heterogeneous family of molecules that can be classified according to their site of action as follows: intracellular, membrane, and extracellular. Representative intracellular antioxidant enzymes are SOD, glutathione peroxidase, and catalase [51-53]. Alpha-tocopherol and coenzyme Q are the main membrane antioxidants [54], whereas metal-binding proteins, such as transferrin and ceruloplasmin, are major extracellular antioxidants that sequester free iron and copper ions that can promote oxidative damage, respectively [55]. In addition, many low-molecular-weight substances that are synthesized in vivo [56] (e.g., melatonin, coenzyme Q, and uric acid) or dietary constituents (e.g., vitamins C and E) exert antioxidant properties [57,58]. These antioxidants have a systematic relationship in the antioxidant network, and they counteract and exhibit synergism [59].

1) Ischemic preconditioning

Among the many interventions against oxidative stress, ischemic preconditioning has been shown to have beneficial effects against hepatic IRI. This preconditioning requires pre-exposure of the liver to brief ischemic episodes to increase its tolerance against subsequent detrimental insults [60]. The underlying molecular mechanism of this intervention is that mild burst oxidants, especially hydrogen peroxide, generated during ischemic preconditioning trigger specific biochemical pathways that ultimately protect against further oxidative damage and lead to adaptation [61]. However, the clinical implications of ischemic preconditioning may be limited because of its invasive properties. Remote ischemic preconditioning is less invasive and more clinically relevant [62]. Remote ischemic preconditioning comprises signal generation from remote organs, signal transfer to target organs, and subsequent protective effects in the target organs. Various neural and humoral factors, such as autonomic ganglion, bradykinin, and adenosine, have been implicated in the pathophysiologic mechanisms of remote ischemic preconditioning [62]. A practical technique has been proposed, which encompasses several brief episodes of ischemia and reperfusion in a remote organ that protects distant targets.

2. Modulation of inflammatory response

As previously mentioned, activation of the immune system is a crucial factor in hepatic IRI, and Kupffer cells and chemoattracted neutrophils are important culprits. Consequently, the cytokine network connected to DAMP contributes to the severity of hepatic IRI via a wave of ROS generation. Consistent with this finding, anti-inflammatory therapy, through various biochemical intersections that inhibit the inflammatory cascade, can attenuate leukocyte recruitment and ROS generation. First, inhibition of DAMP can prevent inflammation and oxidative stress [63]. In addition, administration of a mitochondria-selective S-nitrosylating agent during the acute reperfusion period could prevent mitochondrial ROS bursts and the resulting DAMP release [64]. Further downstream, direct inhibition of Kupffer cells and neutrophils is a promising strategy to treat hepatic IRI [65,66]. In liver transplantation, Kupffer cells are primed in cold ischemic solutions. Subsequently, the primed Kupffer cells exhibit progressive rounding, vacuolization, and degranulation [67]; hence, modulation of Kupffer cell activation plays an important role in reducing IRI in liver transplantation. In contrast, therapeutic modalities to prevent neutrophil recruitment are more diverse due to their multistep processes: chemokine production, expression of adhesion molecules to attach to endothelial cells, and release of effector molecules such as ROS [68]. In a similar context, inhibition of inflammatory cytokines (e.g., TNF-α and IL-1) could be a worthwhile treatment option [38,67]. As TNF-α is a key inflammatory mediator, its neutralization with an antibody and inhibition of its production attenuate hepatic IRI involving neutrophil infiltration [38,69]. Anti-inflammation reduces oxidative stress; conversely, inhibition of ROS and RNS is also a potential therapeutic method for relieving inflammation because these oxidants can activate Kupffer cells and neutrophils, followed by a second wave of ROS and RNS generation. Moreover, inhibition of the complement cascade attenuates hepatic injury [70].

Conclusion

Hepatic IRI occurs in various clinical settings and is a major cause of morbidity and mortality. Although numerous interactions and mediators are involved in its pathophysiology, oxidative stress and inflammatory responses are the main mechanisms. Several therapeutic methods that limit oxidative stress and inflammatory responses have been suggested and applied to attenuate hepatic IRI. If based on a basic understanding of the aforementioned main pathological mechanisms and therapeutic modalities that could improve patient care, our knowledge of these complex hepatic IRI mechanisms remains incomplete.

Notes

Conflicts of interest

No potential conflict of interest relevant to this article was reported.

Funding

None.

Author contributions

Conceptualization: EKC, DGL; Data curation, Methodology: EKC; Formal analysis, Supervision, Validation: DGL; Writing-original draft: EKC; Writing-review & editing: EKC, DGL

Fig. 1.

Pathologic cascade contributing to ischemia and reperfusion injury. Adapted from Kalogeris et al. [2] with permission of Elsevier. ATP, adenosine 5′-triphosphate; ROS, reactive oxygen species; MPT, mitochondrial permeability transition.

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Figure & Data

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