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,
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 (), and the pathways and mediators important in liver ischemia-reperfusion
injury are described ().
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
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, 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
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 (). 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
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
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 (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 ,
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
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
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
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.
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).
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
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
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