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Volume: 7 Issue: 2 June 2009


Inflammatory Mediators of Liver Ischemia-Reperfusion Injury

Liver ischemia and reperfusion — which cause liver damage that is significant in a variety of diseases, injuries, and procedures (including but not limited to trauma and transplant) — have been the focus of many investigations in recent years. Although the mechanisms of ischemia-reperfusion injury are numerous and complex, many advances in treatment have been made. The following review considers recent advances in the understanding of hepatic ischemia-reperfusion injury and focuses on inflammatory mediators of significance. To provide a unique analysis and evaluation, we emphasized the most recent pertinent investigations of the last decade. Specific topics addressed include reactive oxygen species, nitric oxide, toll-like receptors, ischemic preconditioning, T cells, heme oxygenase-1, heat shock proteins, erythropoietin, selectins, protein kinases, matrix metalloproteinases, and cytokines.

Key words : Ischemia and Reperfusion, Inflammatory mediators, Liver, Transplant, Trauma

Ischemia-reperfusion injury, which involves complex inflammatory pathways, is a significant cause of liver damage and an important factor in a variety of diseases, injuries, and procedures that include (but not limited to) transplant and trauma. Several articles have provided an accurate review of the most important factors involved in hepatic ischemia and reperfusion (1,2), such as reactive oxygen species, nitric oxide (3-5), ischemic preconditioning (6), T cells (7, 8), heme oxygenase-1 (9), erythropoietin (10), c-Jun N-terminal kinases (11), matrix metallo­proteinases (12), and chemokines (13). In this report, a comprehensive analysis of those factors is provided, and the fundamental molecular inflammatory mediators present after liver ischemia and reperfusion are discussed. Investigations involving animal models and human trials are reviewed, a summary of significant studies in human subjects is presented (Table 1), and the pathways and mediators important in liver ischemia-reperfusion injury are described (Figure 1).

Reactive Oxygen Species

As liver ischemia ends and reperfusion begins, reactive oxygen species are one of the first elements formed (14). Reactive oxygen species include hydroxyl, the superoxide anion (15), and hydrogen peroxide. All reactive oxygen species respond in varying degrees at the initiation of reperfusion. The peroxidation of lipids (16, 17), protein oxidation, and the formation of peroxinitrites frequently occur after liver ischemia and reperfusion.

Liver ischemia-reperfusion injury is ameliorated by treatment with various free radical scavengers, as shown in investigations of allopurinol, superoxide dismutase, catalase, and other antioxidant compounds. Adenoviral delivery of superoxide dismutase has been shown to produce beneficial effects in warm ischemia reperfusion (18), alcohol-induced liver injury (19), and reduced-size liver grafts (20). The cytosolic superoxide dismutase is reported to be the most effective isoform in transplanted livers (21). Other free-radical scavengers that produce beneficial effects have been studied, including edaravone (MCI-186) (22-26), 2-mercaptoethane sulfonate (27,28), nitronyl nitroxide-amino acid conjugates (29), a-lipoic acid (30), ascorbic acid and mannitol (31), and metalloporphyrins (32). In this discussion of antioxidant molecules, it is also important to include melatonin, which exerts multiple protective effects in hepatic ischemia and reperfusion (33-36). Melatonin has been shown to reduce mitochondrial oxidative stress (37) and increase nitric oxide availability while reducing endothelin expression (38). A decrease in the level of tumor necrosis factor α and the expression of inducible nitric oxide synthase as well as a (possibly) preserved mitochondrial redox status have also been noted as a result of exogenous melatonin treatment (39). Recent evidence has shown that in cases of generalized ischemia after hemorrhagic shock, the effectiveness of melatonin in improving liver function depends on the melatonin receptor (40). In other studies, the beneficial role of melatonin in combination with other antioxidants such as carnosine (41), N-acetylcysteine (42), prostaglandin E1 analogue (43), and, in patients who have undergone partial hepatectomy, resveratrol (44) has been investigated.

Nitric Oxide

Nitric oxide is a free-radical diatomic gas that is produced from arginine (45) by nitric oxide synthase enzymes. Constitutive endothelial nitric oxide synthase and inducible nitric oxide synthase are expressed in liver cells. The process of ischemia and reperfusion is known to cause inducible nitric oxide synthase induction and activation, and there is evidence that interleukin (IL)-1β (46), IL-1 receptor (47), and IL-1 receptor along with nuclear factor-kappa beta (48) may have an important role in that induction. During ischemia and reperfusion, both helpful and harmful effects of nitric oxide have been reported, and the nitric oxide molecule has been described as having a “janus face” (3). These conflicting results about the role of nitric oxide during ischemia reperfusion, with some studies showing beneficial results and others harmful results, have been attributed to the use of nonspecific inhibitors of nitric oxide synthase (49), and it has been noted that whether nitric oxide has a helpful or harmful effect depends on several factors in the liver (4).

General nitric oxide synthase inhibitors have been found to exert a protective effect during liver IR in rats (50), and both endothelial nitric oxide synthase and inducible nitric oxide synthase deficiency have been shown to increase liver injury (51). There is also evidence that during hepatic ischemia and reperfusion, endothelial nitric oxide synthase is protective and inducible nitric oxide synthase is damaging (5). Endothelial nitric oxide synthase has been cited as the source of cytoprotective nitric oxide (52), and endothelial nitric oxide synthase deficiency has been shown to exacerbate injury (53). In other studies, inducible nitric oxide synthase is described as harmful (54-61) on the basis of investigations involving inducible nitric oxide synthase inhibitors (56-60) and inducible nitric oxide synthase knockout mice (61). In a study by Kurabayashi and colleagues, a nitric oxide donor exerted a protective effect by attenuating inducible nitric oxide synthase expression (62), and in another study, inducible nitric oxide synthase inhibitor ameliorated the negative effects of ischemia and reperfusion followed by lipopolysaccharide-induced endotoxemia (63). Nitric oxide production has also been associated with an imbalance in protein tyrosine phosphatases and apoptosis (64), and both nitric oxide and endothelin-1 have been implicated in the dysregulation of sinusoidal perfusion (65). The blockade of arginase has been shown to be beneficial in a murine model of partial warm ischemia reperfusion (66).

In contrast to the evidence of the harmful role of inducible nitric oxide synthase, as cited above, other studies have found a beneficial or inconclusive role for this enzyme. For example, there is evidence that adenovirus inducible nitric oxide synthase pretreatment is protective (67) and that Kupffer cells also protect the liver via an inducible nitric oxide synthase-dependent mechanism (68). In liver injury and fibrosis, the lack of inducible nitric oxide synthase has been associated with increased apoptosis and decreased necrosis and fibrosis (69). Hines and colleagues showed that inducible nitric oxide synthase deficiency produced unanticipated genetic alterations that made mice more susceptible to ischemia and reperfusion (70). A different study showed that the inhibition of inducible nitric oxide synthase produced nonstatistically significant benefits (71).

Lu and associates demonstrated that xanthine oxidase-derived nitric oxide protected the liver against ischemia-reperfusion injury (72). Von Knethen and Brüne (73) studied the activation of peroxisome proliferator-activated receptor gamma by nitric oxide in monocytes and macrophages, and Crosby and colleagues (74, 75) examined the role of peroxisome proliferation-activated receptors in inhibiting inducible nitric oxide synthase. However, the role of nitric oxide during liver ischemia and reperfusion has not been established, and further investigations are needed to characterize that complex and important mediator.

Toll-Like Receptors

Toll-like receptors, which have recently been identified as modulators of liver ischemia and reperfusion (1, 76, 77), are homologues of Drosophila toll proteins that consist of 5 subfamilies (76) with 11 known members in humans. The activation of toll-like receptors results in the production of proinflammatory cytokines and costimulatory molecules (1). Fundamental roles proposed for toll-like receptors include generation of clonal adaptive immune responses, maintenance of normal homeostasis, and noninfectious disease pathogenesis (77).

Activation of toll-like receptor 2 and toll-like receptor 4 has been shown to be involved in the pathogenesis of hepatic ischemia-reperfusion injury. In one study, N-acetylcysteine inhibited that activation and was therefore defined as an agent that mitigates injury (78). According to Zhang and colleagues, inhibition of Kupffer cells is also beneficial because of the down-regulation of toll-like receptor 2 expression (79). Other investigations have found toll-like receptor 4 (but not toll-like receptor 2) to be necessary for the initiation of injury in models of hemorrhagic shock and resuscitation (80) and warm ischemia and reperfusion (81). Shen and colleagues showed that in murine models of orthotopic liver transplant, disruption of toll-like receptor 4 signaling had many beneficial effects (82), and the authors of another investigation suggested that inhibiting the toll-like receptor 4/nuclear factor-kappa beta pathway minimizes ischemia-reperfusion injury (83). In a plasmid expressed model, the IL-1–like protein ST-2 exerted a beneficial effect on warm hepatic IR injury, possibly by suppressing the toll-like receptor 4 pathway (84). Toll-like receptor 4 activation has been found to contribute to ischemia-reperfusion injury because of the release of tumor necrosis factor α (85), including lipopolysaccharide activation of toll-like receptor 4 (86), and in another study, toll-like receptor 4-deficient mice had less hepatic injury with the regulation of tumor necrosis factor α messenger ribonucleic acid reported as a critical effect (87). Carbon tetrachloride-induced injury has been shown to up-regulate the gene expression of toll-like receptor 4 (88). Tsung and colleagues demonstrated that the activation of actively phagocytic cells, like Kupffer cells, by toll-like receptor 4 is required for warm ischemia-reperfusion injury and inflammation (89). Those authors also showed that the nuclear protein high-mobility group box 1, a key alarm molecule during liver ischemia and reperfusion, is associated with toll-like receptor 4 signaling (90, 91).

Overall, the role of toll-like receptors during liver ischemia and reperfusion has not been completely defined. More studies are required to provide further information about those receptors and their interactions with other important molecules.

Ischemic Preconditioning

Ischemic preconditioning, which is a proposed method for reducing organ ischemia-reperfusion injury, involves exposing the organ to a brief period of ischemia (6), which will induce protective effects that will be beneficial during the more prolonged subsequent period of ischemia. Data concerning ischemic preconditioning are still inconclusive (92) and conflicting (93), and the precise mechanisms of that therapy are unknown (94).

Using ischemic preconditioning during ischemia and reperfusion has been shown to be beneficial in human subjects, resulting in less ischemic injury and fewer complications after hepatic resection (95) and in murine models of cirrhosis (96) and rat models of fatty liver disease (97). In a randomized controlled trial, 10 minutes of ischemic preconditioning was protective against ischemia-reperfusion injury in patients undergoing deceased donor transplant (98), and the results of another investigation suggested that ischemic preconditioning protects deceased donor allografts and reduces the nonspecific inflammatory response (99). However, Koneru and colleagues showed that ischemic preconditioning increased hepatic injury in recipients of a deceased donor liver transplant, although those authors acknowledged that their results conflicted with the findings of studies on elective hepatic surgery (93).

Various mechanisms that explain the beneficial effects of ischemic preconditioning have been identified (Table 2). The attenuation of nuclear factor-kappa beta and subsequent reduction of tumor necrosis factor α expression (94) or a reduction in oxidative stress, which protects mitochondria (100), are 2 such reported mechanisms. Other potential mechanisms include the stimulation of Kupffer cell-produced reactive oxygen species and liver regeneration via the A2 (adenosine) receptor pathway in Kupffer cells (101). The increased formation of A2 and the attenuated degradation of adenine nucleotides to purines (102) have been documented as well. Activation of the p38 protein and concomitant preservation of intracellular glutathione levels are essential for the development of hydrogen-peroxide resistance in preconditioned livers, although it has been shown that the A2 receptor is not essential for that process (103). Ischemic preconditioning was also found to reduce neutrophil activation in humans (104). IL-6 is reported to be a key mediator of protective effects in ischemic preconditioning (105). More specifically, that protection depends on IL-6 and its associated increased phosphorylation of signal transducer and activator of transcription 3 (106). Furthermore, cardiotrophin-1, a cytokine of the IL-6 family, has been shown to be a key mediator of the protective effects of ischemic preconditioning (107). Other data have suggested that suppression of tumor necrosis factor α may be involved in the protective mechanism of ischemic preconditioning against hepatic ischemia reperfusion injury (108).

In a study by Massip-Salcedo and colleagues, levels of heat shock protein 72 and the enzyme heme oxygenase-1 were elevated at 6 and 24 hours of reperfusion, respectively, as a result of ischemic preconditioning (109). Tyrosine kinases have been implicated as being involved in the ischemic preconditioning response (110), and protein kinase C is reported to be essential in studies of cold preserved hepatic grafts (111). Furthermore, the role of tyrosine kinases in ischemic preconditioning may be mediated by nuclear factor-kappa beta, but the effects of protein kinase C were found not to be dependent on nuclear factor-kappa beta (112).

Alternatives to traditional ischemic pre-conditioning, such as stepwise rising carbon dioxide insufflation (113) and preconditioning with death ligands (114), emulsified isoflurane (115), or high-mobility group box 1 (116), and their possible beneficial effects have been investigated. The possible benefits of ischemic preconditioning are still a topic of debate, however. An investigation of liver transplants in pigs revealed no statistically significant beneficial effects of ischemic preconditioning, and the authors therefore called for further studies of the ischemic preconditioning process. (117). A study of deceased donor liver transplants showed that although ischemic preconditioning resulted in better tolerance to ischemia than did a standard orthotopic liver transplant, there was also decreased early function in the transplants treated with ischemic preconditioning. Those authors concluded that the clinical value of ischemic preconditioning remains uncertain (118). A recent Cochrane database review demonstrated that there is currently no evidence to support or refute the use of ischemic preconditioning in donor liver retrievals, and the authors suggested that further studies, including further clinical trials, are needed (6). DeOliviera and colleagues recently stated that in contrast to experimental studies using ischemic preconditioning, clinical studies include parameters that are much more heterogeneous and that there is still much to investigate in this area (92).

T Cells

Recent review articles have drawn attention to the importance of T cells in ischemia and reperfusion injury (7, 8). According to an emerging view, those cells can regulate liver ischemia-reperfusion–induced inflammation and can serve as novel targets for interventions (7). Because there is evidence that T cells have divergent roles in different phases of ischemia-reperfusion injury, their overall role in the ischemia reperfusion process is likely complicated (8). For example, although CD4+ T cells recruit neutrophils via IL-17, they also appear to attenuate neutrophil activation (119). Considering the ways in which T cells can function during ischemia-reperfusion injury, given the absence of exogenous antigens, it has been determined that CXCR3 chemokine biology has a critical role in the pathophysiology of hepatic ischemia reperfusion injury (120).

The immunosuppressant fingolimod has been shown to ameliorate hepatic ischemia and reperfusion injury by preventing T-cell infiltration (121). Other studies of T-cell costimulation via CD154-CD40 have identified that process as a potential therapeutic target (122, 123). Natural killer T cells have been implicated in ischemia-reperfusion damage, possibly due to their cytotoxicity (124). CD4 T cells have been shown to aggravate microvascular and hepatocellular injury by activating the endothelium and by increasing platelet adherence and neutrophil migration (125). In one study, the antagonism of IL-12 produced a beneficial effect by restoring apoptosis within peripheral T cells (126).

ATL-146e, an adenosine A2A receptor agonist, has been shown to produce beneficial effects such as the inhibition of the CD1d-dependent activation of natural killer T cells (127) and the concanavalin A activation of T cells (128). After ischemia and reperfusion, cyclo-oxygenase-2–deficient mice exhibited a significant reduction in liver damage, and the deficiency in cyclo-oxygenase-2 was found to favor a Th2 response (129). Furthermore, it has been suggested that the early expression of Th2 cytokines may contribute to the attenuation of liver ischemia-reperfusion injury in humans (130). The connecting segment-1 peptide blocks fibronectin-alpha4beta1 integrin interactions. Two studies have shown that treatment with connecting segment-1 significantly inhibited the recruitment of T cells and other factors that contribute to ischemia-reperfusion injury in rat models of orthotopic liver (131) and fatty liver transplants (132).

Heme oxygenase-1

Heme oxygenase-1 (heat shock protein 32) is an inducible rate-limiting enzyme that catalyzes the reaction of heme to carbon monoxide, iron, and biliverdin. Heme oxygenase-1 expression has been reported to be protective against various forms of stress and has therefore been considered for the treatment of several pathologic conditions (9).

Heme oxygenase-1 induction has been shown to be protective in cases of hepatic ischemia-reperfusion injury and in the reduction of oxidative stress, apoptosis, and inflammation in cirrhotic livers (133). Studies have used heme oxygenase-1 inducers and antagonists. The cobalt protoporphyrin induction of heme oxygenase-1 has been shown to improve liver function (including suppression of type 1 interferon) and histologic characteristics (134). Another investigation using cobalt protoporphyrin and the heme oxygenase-1 antagonist zinc protoporphyrin demonstrated the protective effects of heme oxygenase-1 induction during the prolonged storage of liver transplants (135). In one study, hypertonic saline prevented ischemia-reperfusion injury by promoting the expression of heme oxygenase-1 (136), and in another investigation, induction with simvastatin preconditioning also had a protective result (137). In a study by Coito and colleagues, adenoviral heme oxygenase-1 gene transfer inhibited inducible nitric oxide synthase, prolonged the survival of steatotic orthotopic liver transplant in rats (138), and prevented CD95/FasL-mediated apoptosis (139). Heme oxygenase-1 overexpression has also been associated with decreased CXC chemokine ligand 10 expression (140). Heme oxygenase-1 has been studied in carbon-tetrachloride–induced liver damage, and induction had a possible protective effect (141, 142) in a study with glycyrrhizin, the major active component extracted from licorice (143). However, other data on carbon tetrachloride injury showed that a harmful effect resulted from higher heme oxygenase-1 activity (144). In a study of cold ischemia and reperfusion by Wang and colleagues, heme oxygenase-1 overexpression was protective, an effect that was attributed, at least in part, to modulation of the antiapoptotic pathway (145).

Finally, there is evidence that treatment with the products or related molecules of the heme oxygenase-1 reaction is protective, including biliverdin [146], bilirubin (147), and carbon monoxide. Specifically, exogenous carbon monoxide was protective in liver transplants (148, 149) and in carbon-tetrachloride–induced hepatic injury (150). There is also evidence that heme oxygenase-1 mediated cytoprotection depends on and can be substituted by carbon monoxide generation (151).

Heat Shock Proteins

Heat shock proteins, a class of molecular chaperones (particularly heat shock proteins 70 and 72), are reportedly involved in hepatic ischemia-reperfusion injury. In steatotic livers subjected to heat shock protein preconditioning, preventing the postischemic failure of microcirculation was associated with the induction of heat shock protein 72 and heme oxygenase-1 (152). Heat shock protein preconditioning also reduced the oxidative injury of cellular proteins and deoxyribonucleic acid (153).

The protective effects of other substances are also associated with heat shock protein induction. Prostaglandin E1 has been shown to induce heat shock proteins immediately after ischemia and reperfusion (154), and the mechanism of curcumin protection might be associated with the overexpression of heat shock protein 70 and antioxidant enzymes (155). In a study by Bedirli and colleagues, the natural antioxidant ergothioneine protected the liver by inducing the overexpression of heat shock protein, which caused the subsequent suppression of lipid peroxidation (156). The protective effects of 17beta-estradiol may be related to the overexpression of heat shock protein 70 (157). With regard to the apoptosis of hepatocytes caused by hydrogen peroxide and ethanol, geranyl­geranylacetone has been shown to exert an antiapoptotic action, at least in part via the priming of hepatocytes for enhanced heat shock protein 70 induction (158). Shi and colleagues demonstrated that quercetin pretreatment delayed liver regeneration via the inhibition of heat shock proteins (159), and although glutamine has been shown to be protective in ischemia-reperfusion in other tissues, its lack of effectiveness in the liver was attributed by Noh and colleagues to an absence of heat shock protein 70 up-regulation (160). In warm ischemia and reperfusion, the expression of heat shock protein 70 and the Bcl-2 family were found to be effective markers of viability (161), and in cold preservation, the beneficial effects of doxorubicin (162) and zinc (163) were associated with heat shock protein induction. Heat shock protein 70 induction during ischemia and reperfusion injury has been associated with a prompt reduction in the levels of transaminases and the rapid recovery of fibrinogen (164).

In considering the possible downstream effects of heat shock proteins during ischemia and reperfusion, heat shock protein preconditioning protected the liver by suppressing nuclear factor-kappa beta and stabilizing I-kappa beta in a study by Uchinami and colleagues (165), and heat shock protein inhibition of the activation of nuclear factor-kappa beta may have been protective in cold ischemia and reperfusion in an investigation by Chen and colleagues (166). Induced heat shock protein 70 may affect the Bcl-xL level, which seems to be involved in the reduction of liver damage (167). Intracellular heat shock protein has been found to be directly hepatoprotective, but Kuboki and colleagues showed that extracellular heat shock protein was not a significant contributor to hepatoprotection (168). Recent evidence has demonstrated that extracellular heat shock protein 72 binds to toll-like receptors 2 and 4, which then signal through nuclear factor-kappa beta to increase macrophage inflammatory protein 2 production. According to Galloway and colleagues, the time at which heat shock protein 72 is available to hepatocytes may determine the overall effect of that protein on the response to injury (169).


Erythropoietin is involved in more than just erythropoiesis. Interest in the cytoprotective features of this glycoprotein hormone is increasing at an almost exponential rate (170). Erythropoietin may have potential benefits for patients with any of a wide variety of disorders (Alzheimer disease, cardiac insufficiency, stroke, trauma, complications of diabetes) (171). The potential neuroprotective and cardioprotective roles of erythropoietin (independent of its hematopoietic action) against ischemia have also been documented (10).

Research has suggested that erythropoietin is effective in reducing hepatic ischemia-reperfusion injury and that the preischemic administration of erythropoietin exerts a protective effect (172). In a study by Hochhauser and colleagues, pretreatment with 1 dose of recombinant human erythropoietin attenuated postischemia-reperfusion hepatocyte apoptotic damage, and the modulation of nuclear factor-kappa beta and c-Jun N-terminal kinase may have had a role in those protective effects (173). When recombinant human erythropoietin was administered 5 minutes before ischemia in a study by Sepodes and colleagues, biochemical evidence of liver injury was reduced, but that effect was not noted when recombinant human erythropoietin was administered 5 minutes before reperfusion (174). In a model of warm hepatic ischemia and reperfusion, the data suggested a protective effect from erythropoietin administration and showed that the results of intraportal venous injection were superior to those of subcutaneous preconditioning (175). In fetal rats, administration of recombinant human erythropoietin-reduced thiobarbituric acid-reactive substances induced lipid peroxidation (176).

Noting that recombinant human erythropoietin had been studied in liver ischemia, but not in hepatic resection and regeneration, Schmeding and colleagues showed that recombinant human erythropoietin increased liver regeneration in rats after a 70% liver resection and enhanced survival in that model after a 90% hepatectomy (177). Both erythropoietin and mitochondrial potassium channel openers have exerted protective effects in liver ischemia-reperfusion injury. Yazihan and colleagues found that the potassium channel inhibitor glibenclamide reduced the protective effects of erythropoietin during hydrogen peroxide toxicity in hepatocytes (178). In a study of laparoscopically induced oxidative injury, preischemic administration of erythropoietin decreased oxidative injury, but not as much as laparoscopic preconditioning (179).

Further studies of the role of erythropoietin in various cytoprotective processes, including liver ischemia-reperfusion injury, will clarify the dynamic effects of this important mediator.

Selectins are cellular adhesion molecules. During ischemia and reperfusion injury, they are involved in both cellular infiltration and molecular signaling (180). There are 3 types of selectins: E, L, and P. With respect to leukocyte recruitment into inflamed liver sinusoids, selectins are not required in all instances, but they are required in ischemia and reperfusion (181). Investigators have found that interfering with P-selectin produces a protective effect against liver ischemia reperfusion injury. In a study of warm ischemia and reperfusion by Khandoga and colleagues, P-selectin deficiency prevented microvascular injury and apoptosis (182). Blocking the P-selectin glycoprotein ligand-1 with an antibody has been shown to be a simple and effective strategy for protecting against ischemia reperfusion injury in models of cold ischemia liver transplant (183). The recombinant P-selectin glycoprotein ligand-1 immunoglobulin blockade of CD-62-mediated adhesive interactions reduced ischemia-reperfusion injury in steatotic rat livers in an investigation by Amersi and colleagues (184). The addition of a lipid-soluble iron chelator substantially increased the protection provided by recombinant P-selectin glycoprotein ligand-1 immunoglobulin alone, as demonstrated by Amersi and colleagues in another study (185). Dendritic cells may have an important role in hepatic or renal ischemia-reperfusion injury, and anti-P-selectin lectin-epidermal growth factor domain monoclonal antibody may inhibit local dendritic cell migration and accumulation (186). In cases of uncontrolled hemorrhagic shock, the blockade of L-selectin has been associated with decreased hepatocellular injury and increased survival (187). Some authors have suggested that the improved hemodynamics and decreased leukocyte adherence occurring after treatment with N-acetylcysteine might result from the shedding of selectins (188).

In some models of hepatic ischemia and reperfusion, hepatocellular injury was independent of P-selectin and intercellular adhesion molecule-1 (189). It has been suggested that because of compensation by uninhibited cell-adhesion molecules, treatments that target only a single selectin can be ineffective (180). Protective results, including a significant decrease in the level of serum tumor necrosis factor α, an equally significant increase in the level of serum-protective IL-10 (190), and an increase in the modulation of protein kinases and chemokines (191), have been reported after treatment with the multiselectin blocker Texas Biotechnology Corporation (TBC)-1269. In addition, the multiselectin inhibitor OC-229 provided both functional and histologic protection of the ischemic liver, including dissociation of nuclear factor kappa beta and activator protein 1 activity, with a reduction in the activity of activator protein 1 and an increment in nuclear factory kappa beta activation. (192).

Protein Kinases

We will now consider some of the literature pertaining to the role of protein kinases in liver ischemia-reperfusion injury. A mitogen-activated protein kinase, c-Jun N-terminal kinase, has been reported to have a role in the mechanism of ischemia-reperfusion injury (193). Dysregulated c-Jun N-terminal kinase signaling is also believed to contribute to many other disorders, including those involving neurodegeneration, chronic inflammation, birth defects, and cancer (11). It has been suggested that the generation of reactive oxygen species during hypoxia directly activates c-Jun N-terminal kinase in a Rac-1-dependent process (194). c-Jun N-terminal kinase inhibitors were shown to exert protective effects in liver ischemia and reperfusion and were associated with decreased necrosis and apoptosis (195, 196). Tacrolimus (FK506) also reduced ischemia-reperfusion–induced apoptosis and necrosis, including reduced c-Jun N-terminal kinase 1/stress-activated protein kinase 1 and caspase 3 activation (197). Lee and associates showed that c-Jun N-terminal kinase inhibitors exacerbated hepatic ischemia-reperfusion injury (198). Those authors acknowledged that their results differed from the findings of other studies, and while they could not provide a definitive explanation for the discrepancy, they cited possible differences in dosing schedules as a potential explanation.

Other mitogen-activated protein kinases have been studied in addition to c-Jun N-terminal kinase. In a study by Zhao and colleagues, fingolimod decreased ischemia-reperfusion injury by activating Akt signaling and down-regulating the mitogen-activated protein kinase pathway (199), which led to the down-regulation of early growth response-1 (200). The inhibition of p38 has been shown to produce protective effects (201). In 2007, Kobayashi and colleagues reported on the beneficial effects of p38 activation, but stated that the role of mitogen-activated protein kinase is controversial and depends on several factors (202). Investigations have considered the small GTPase Rho and the effector Rho kinase. In studies of Rho inhibitors, protective effects such as a reduction in the generation of reactive oxygen species and the suppressed release of inflammatory cytokines (203), the amelioration of postischemic microcirculation (204), the suppression of polymorphonuclear leukocytes and inflammatory cytokines (205), prolonged survival (206), inhibited contraction of hepatic stellate cells (207), and reduced damage in carbon tetrachloride-induced injury (208) have been reported. In hepatocytes, the adenoviral-mediated overexpression of double-negative Rho kinase has been shown to suppress the production of reactive oxygen species and the release of proinflammatory cytokines, and to significantly prolong survival (209).

Matrix Metalloproteinases

The matrix metalloproteinases are zinc-dependent endopeptidases. The 24 human matrix metallo­proteinases are one of the major families of proteinases that have an important role in the responses of cells to their microenvironment, including the combined ability to degrade all components of the extracellular matrix (210).

Studies have shown that matrix metallo­proteinases have an important role in liver ischemia-reperfusion injury, and remaining challenges include defining their mechanism of activation and targets (211). By altering the extracellular matrix, matrix metalloproteinases also have a major role in cold ischemia- warm reperfusion injury. Therefore, their inhibition might be a new strategy for improving preservation solutions (212). Because matrix metalloproteinases and their tissue inhibitors are released and activated during ischemia and reperfusion, the imbalance of those substances has been shown to contribute to the fibrosis that can occur after liver injury (12). The therapeutic effects of inhibiting matrix metalloproteinases have been documented in histologic studies and analyses of serum hepatic enzyme levels (213) and shown in the inhibition of gelatinolytic activity and the decreased release of inflammatory cytokines (214). In a study by Chen and colleagues, reperfusion injury induced an increase in the level of matrix metalloproteinase-9, and oxygen radical production was implicated in matrix metalloproteinase expression and liver injury (215). In humans, only matrix metalloproteinase-9 seems to be involved in ischemia-reperfusion injury during liver transplant, and nonserine-protease/plasmin pathways have been shown to be involved in matrix metalloproteinase regulation (216). In another study in human subjects, matrix metalloproteinase-2 and matrix metalloproteinase-9 were not associated with the late phase of liver ischemia-reperfusion injury (217).

In steatotic liver grafts, T cells, monocytes, and macrophages have been defined as the main sources of matrix metalloproteinase-9, the up-regulation of which has been associated with impaired liver function (218). Matrix metalloproteinase-9–specific inhibition is a critical element in leukocyte recruitment and activation; this suggests that matrix metalloproteinase-9 inhibition is a potential therapeutic target (219). In another report, matrix metalloproteinase-9 blockade was associated with the attenuation of tumor necrosis factor α release and endothelial CD62P expression, which improved postischemic survival (220).

Cytokines and Chemokines

Cytokines and chemokines, which are important mediators of hepatic ischemia-reperfusion injury, produce both harmful and beneficial effects. In ischemia and reperfusion, chemokines reportedly influence the activity of neutrophils, macrophages, and T cells (221). The CXC chemokine ligand 10 regulated liver inflammation in a study in which CXC chemokine ligand 10 knockout mice sustained less hepatic injury (13). Involvement of IL-1 and its receptor in the induction of inducible nitric oxide synthase was previously discussed in this review (46-48), and gene delivery of the IL-1 receptor was potentially helpful in reducing ischemia-reperfusion injury after transplant in a study by Harada and colleagues (222). Data have shown that the interferon type 1 (but not type 2) pathway is required for ischemia-reperfusion–triggered liver inflammation and damage (223).

IL-12 facilitates cell-mediated cytotoxicity. Dimaprit, a histamine agonist, was shown to exert protective effects, possibly by decreasing the level of released IL-12 (224), and the proinflammatory effects of IL-12 have been found to be independent of signal transducer and activation of transcription 4 (STAT-4) (225). A dual inhibitor of IL-1 and tumor necrosis factor α decreased liver injury in a study by Takiguchi and colleagues (226), and Ben-Ari and colleagues showed that monoclonal antibodies against tumor necrosis factor α attenuated postischemic injury (especially apoptosis) (227). The suppression of tumor necrosis factor α has also been identified as a possible protective mechanism in ischemic preconditioning (108). IL-18 was found to suppress anti-inflammatory cytokines during hepatic ischemia-reperfusion injury (228). Tumor necrosis factor α exerts pleiotropic effects on the liver. In a transplant model, Conzelmann and colleagues showed that the graft tumor necrosis factor receptor-1 decreased graft injury and recipient tumor necrosis factor receptor-1 increased injury (229).

Cytokines also exert beneficial effects. Guidi and colleagues found that during ischemia, IL-6 levels were significantly increased (230), and IL-6 has been implicated as a likely mediator of protective effects during ischemic preconditioning (105,106). The adenoviral-based gene transfer of IL-10 has been shown to protect the liver (231), and in studies by Ke and colleagues (232) and Oreopoulos and colleagues (233), hypertonic saline solution attenuated hepatic ischemia and reperfusion injury by increasing the release of IL-10. Kawakami and colleagues showed that recombinant human IL-11 protects against carbon tetrachloride-induced liver injury by heme oxygenase-1 induction (234), and Kato and colleagues demonstrated that IL-13 exerts prominent protective effects for hepatocytes and endothelial cells (235).


Although the complex pathways involved in hepatic ischemia-reperfusion injury have yet to be completely elucidated, much progress has been made in recent years. Past, current, and future investigations of reactive oxygen species, toll-like receptors, leukocyte-endothelial interactions, the heme oxygenase system, nitric oxide, and other molecules listed in this review are crucial to understanding the roles of those mediators and their interactions. More extensive studies of ischemic preconditioning are warranted, because some of those conducted to date have not been as successful as expected. The definitive management of liver ischemia-reperfusion injury has not been established, even though multiple downstream pathways and well-identified cascades are already known. In future investigations, a greater understanding of all factors involved will enable more effective treatment for liver ischemia-reperfusion injury.


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Volume : 7
Issue : 2
Pages : 78 - 93

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From the 1Michigan State University College of Human Medicine, East Lansing, Michigan; the
2Division of Abdominal Transplantation, University of North Carolina, Chapel Hill, North Carolina;
3University of Texas Southwestern Medical Center;
4University of Baja California Medical School, Mexicali, B. C. Mexico; and
5Kalamazoo Center for Medical Studies, Michigan State University, Kalamazoo, Michigan
Address reprint requests to: Luis H. Toledo-Pereyra, MD, Kalamazoo Center for Medical Studies, Michigan State University, 1000 Oakland Drive, Kalamazoo, MI 49008
Phone: +1 269-337-6010
Fax: +1 269-337-4609