Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205
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ABSTRACT |
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Ischemia-reperfusion injury is, at least in part, responsible for the morbidity associated with liver surgery under total vascular exclusion or after liver transplantation. The pathophysiology of hepatic ischemia-reperfusion includes a number of mechanisms that contribute to various degrees in the overall injury. Some of the topics discussed in this review include cellular mechanisms of injury, formation of pro- and anti-inflammatory mediators, expression of adhesion molecules, and the role of oxidant stress during the inflammatory response. Furthermore, the roles of nitric oxide in preventing microcirculatory disturbances and as a substrate for peroxynitrite formation are reviewed. In addition, emerging mechanisms of protection by ischemic preconditioning are discussed. On the basis of current knowledge, preconditioning or pharmacological interventions that mimic these effects have the greatest potential to improve clinical outcome in liver surgery involving ischemic stress and reperfusion.
Kupffer cells; neutrophils; complement; adhesion molecules; reactive oxygen; nitric oxide; apoptosis; cytokines; chemokines
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INTRODUCTION |
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LIVER DYSFUNCTION OR FAILURE is still a significant clinical problem after transplantation surgery, tissue resections (Pringle maneuver), and hemorrhagic shock. Despite the significant improvement of clinical outcome during the last decade, the dramatic organ shortage for transplantation forces consideration of cadaveric or steatotic grafts, which have a higher susceptibility to ischemia-reperfusion injury. Although substantial progress has been made in elucidating mechanisms of ischemia-reperfusion injury, there is still a need to better understand the pathophysiology. The current review will summarize established basic concepts of reperfusion injury in the liver together with recent new insights into injury mechanisms and novel therapeutic strategies. Due to the complexity of the overall process, this review can only provide an in-depth discussion on selected aspects of the pathophysiology. For areas not sufficiently covered, the reader is referred to other, excellent reviews (11, 93, 99, 116, 147).
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THE INFLAMMATORY RESPONSE DURING REPERFUSION: CELLULAR MECHANISMS AND OXIDANT STRESS |
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An excessive inflammatory response is clearly recognized as a key
mechanism of injury during reperfusion (53, 54).
Ischemia activates Kupffer cells (Fig.
1), which are the main sources of vascular reactive oxygen formation during the initial reperfusion period (59, 63, 136). Interestingly, this effect is only observed after no-flow ischemia (Pringle, transplantation) but not after hemorrhagic shock, i.e., low-flow ischemia
(62). In addition to Kupffer cell-induced oxidant stress,
with increasing length of the ischemic episode, intracellular
generation of reactive oxygen by xanthine oxidase and in particular
mitochondria (39, 42, 71) may also contribute to liver
dysfunction and cell injury during reperfusion (39, 83).
In addition, the presence of a phagocyte-type NADPH oxidase was
recently recognized as a major source of superoxide formation in
endothelial cells (97) and hepatocytes (126).
Rac1, a member of the Rho family of small GTPases, regulates this
enzyme. Inhibition of Rac1 attenuated the intracellular oxidant stress
during the early reperfusion phase and protected against liver injury
(126). Proinflammatory cytokines, chemokines, and
activated complement factors are responsible for neutrophil recruitment
and the subsequent neutrophil-induced oxidant stress during the later
reperfusion phase (60). Stimulation of primed Kupffer
cells by complement factors causes the continuous activation of these
macrophages (60, 64). The Kupffer cell- and
neutrophil-induced oxidant stress is an important factor in vascular
and parenchymal cell injury during reperfusion (63, 65,
67). The relevance of this postischemic vascular oxidant stress was demonstrated by the protective effect of extracellular glutathione (GSH) (14, 58, 100), which can scavenge
hydrogen peroxide, hypochlorous acid, and peroxynitrite (13, 77,
100). Despite the mainly vascular origin of the oxidant stress,
reactive oxygen generated by Kupffer cells (12) or
adherent neutrophils (70) causes a substantial
intracellular oxidant stress in hepatocytes. Animals deficient in
glutathione peroxidase are significantly more susceptible to
neutrophil-induced oxidant stress than wild-type animals
(70). This suggests that intracellular defense mechanisms are critical for detoxification of reactive oxygen species generated by
intracellular as well as extracellular sources. This mechanism explains
why antioxidants targeted to either extracellular or intracellular
sites attenuated reperfusion injury in the liver (12, 55, 100,
164, 168, 178).
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A topic of substantial controversy during the last two decades was the
discussion about the molecular mechanism of injury (Fig.
2). Initially, it was assumed that any
postischemic oxidant stress leads to cell death by lipid
peroxidation. However, lipid peroxidation is quantitatively
insufficient to explain the severe cell injury during reperfusion
(109). Inflammatory cells also release proteases, which
may be the actual cytotoxic mediators of neutrophils
(110). The beneficial effect of protease inhibitors supported a role of proteases in the pathophysiology of reperfusion injury in experimental models (86, 98) and in humans
(76). In fact, it was hypothesized that the role of
reactive oxygen species in an inflammatory injury in vivo is actually
not to cause cell injury but to inactivate anti-proteases of the plasma
by oxidation in the vicinity of the neutrophil (163). This
would allow neutrophil-derived proteases to act locally without
interference of anti-proteases. On the other hand, proteases, which
escape into the circulation, can still be inactivated to prevent
systemic vascular injury (163). However, more recent data
clearly indicate that Kupffer cells (12) and neutrophils
(70) can kill hepatocytes in vivo by reactive oxygen
species. In general, oxidant stress-induced cell killing involves
oxidation of pyridine nucleotides, accumulation of calcium in
mitochondria, and superoxide formation by mitochondria, which
ultimately leads to formation of membrane permeability transition pores
and breakdown of the mitochondrial membrane potential (121, 122). In support of this intracellular signaling mechanism, the mitochondrial membrane permeability transition was observed during hepatic ischemia-reperfusion (29, 88, 130).
Pharmacological inhibition of the mitochondrial membrane permeability
transition protected against reperfusion injury (29, 42, 73,
88). Thus in an acute attack by Kupffer cells and neutrophils,
proteases may not be necessary to cause hepatocellular necrosis. On the other hand, during a prolonged neutrophil response over several days,
the injury may be caused by a combination of reactive oxygen and
proteases (Fig. 2).
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In addition to the inactivation of anti-proteases and the direct
cytotoxic effects, reactive oxygen can promote reperfusion injury
through stimulation of the transcription factors NF-B and activator
protein-1 (AP-1) (34, 56). The postischemic oxidant stress can enhance the expression of genes, such as TNF-
, inducible nitric oxide (NO) synthase (iNOS), heme oxygenase-1, CXC
chemokines, and adhesion molecules. On the other hand, antioxidants attenuate proinflammatory gene expression through inhibition of NF-
B
and AP-1 activation (8, 32, 70, 132, 181).
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NO: PREVENTION OF MICROCIRCULATORY DISTURBANCES VS. PEROXYNITRITE FORMATION |
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The NO radical is generated in the liver by constitutively expressed endothelial NOS (eNOS) or iNOS. Whereas eNOS is only expressed in sinusoidal endothelial cells (175), iNOS can be transcriptionally upregulated in endothelial cells, hepatocytes, and other liver cell types (175). NO is a potent vasodilator, which diffuses freely across cell membranes and acts intracellularly by activation of guanylate cyclase. In response to vasoconstrictors, NO can induce vasodilation at the level of the sinusoid as well as at presinusoidal sites (112, 117, 165). In addition to its vasodilatory effect, NO reacts with superoxide to form the potent oxidant peroxynitrite (144). In fact, superoxide reacts much faster with NO than with superoxide dismutases (144). In general, it has been assumed that eNOS-derived NO is responsible for maintaining liver blood flow and excessive NO formation by iNOS may lead to peroxynitrite-induced injury as well as systemic effects, such as hypotension and shock (152).
Microcirculatory disturbances and nonperfused sinusoids are well-recognized phenomena that contribute to reperfusion injury after hepatic ischemia (21, 81, 155). Although vascular lining cell injury and intravascular coagulation can reduce or block blood flow in sinusoids and cause liver injury, active vasoconstriction is also a major contributing factor (112, 113). In particular, endothelins have been identified as the most potent vasoconstrictors generated during reperfusion (40, 119). In addition, increased expression of the ETB receptor during reperfusion confers an increased responsiveness of the hepatic vasculature to endothelins (171). Therefore, endothelin receptor antagonists were shown to attenuate reperfusion injury in the liver (40, 79). These observations indicate that insufficient amounts of NO are produced to effectively counteract the enhanced vasoconstrictive state during reperfusion. In support of this hypothesis, it has been shown that any NOS inhibitor that affects eNOS reduces microvascular perfusion and aggravates liver injury during endotoxemia (123) and ischemia-reperfusion (44, 161). These data were recently confirmed in eNOS gene knockout mice (46, 89). All detrimental effects of eNOS inhibition can be completely reversed by exogenous NO-donors (134, 135, 161). Interestingly, NO protects under these conditions despite the increased formation of peroxynitrite (103, 161). This would suggest that the beneficial effects of maintaining liver blood flow by far outweigh the potential for cell damage by peroxynitrite. On the other hand, excessive NO formation after endotoxin-induced iNOS gene expression causes increased injury by peroxynitrite formation and systemic hypotension, which reduces liver blood flow (152). Although we could confirm the reported beneficial effects of a selective iNOS inhibitor in endotoxemia, the same inhibitor reduced microvascular blood flow and enhanced liver injury during hepatic ischemia-reperfusion (160). These findings, which were recently confirmed (50), suggest a potential role of iNOS in maintaining liver blood flow during reperfusion. However, others reported no effect of iNOS-derived NO on reperfusion injury (47, 135) or even a beneficial effect of a novel iNOS inhibitor (115). Similarly, mice deficient in iNOS showed a moderate reduction of reperfusion injury (89). However, some of the protective effects of iNOS inhibition were observed well before iNOS induction (89, 115). This raises the possibility that other effects of the drugs or compensatory mechanism for iNOS deficiency have to be considered (46). Independent of the source of NO, the available data in the literature indicate that in the postischemic liver, a new equilibrium is established between the increased vasoconstrictor formation and enhanced responsiveness on the one hand and the formation of NO as a countermeasure to maintain microvascular blood flow.
Despite the increased superoxide and NO formation during reperfusion, there is only little evidence for peroxynitrite generation with no obvious pathophysiological relevance (103, 161). The reason for the limited importance of peroxynitrite in hepatic ischemia- reperfusion injury might be the critical role of NO in preventing excessive vasoconstriction and the fact that glutathione, a potent scavenger of peroxynitrite, is available in sufficient concentrations intra- and extracellularly to prevent tissue damage (77). In addition, other beneficial effects of NO, such as protection of mitochondria and induction of heat shock proteins, may also be involved (162).
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NEUTROPHIL RESPONSE DURING REPERFUSION: CELLULAR ADHESION MOLECULES |
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During the development of the early reperfusion injury,
neutrophils are recruited into the liver vasculature, are activated, and then cause aggravation of reperfusion injury (67). For
neutrophil accumulation at a site of inflammation, several families of
CAMs are involved (41). Initial tethering of neutrophils
in postcapillary venules requires expression of selectins on
endothelial cells and interaction with their counter-receptors on
neutrophils. Subsequent activation of 2 integrins on
neutrophils by chemotactic factors and upregulation of ICAM-1 on
endothelial cells leads to the firm adhesion of neutrophils on the
endothelial surface followed by extravasation and migration to the
inflammatory site (41). However, this general scheme is
only partially applicable to the postischemic liver (Figs. 1
and 2). The liver has two principal vascular beds for neutrophil
accumulation during reperfusion: sinusoids and postsinusoidal venules
(157). Venular endothelial cells can upregulate P-selectin
expression by mobilizing preformed molecules from Weibel Palade bodies
(137). In addition, P- and E-selectin as well as ICAM-1
and VCAM-1 can be transcriptionally upregulated (52). Sinusoidal endothelial cells do not contain Weibel Palade bodies and do
not form relevant amounts of P-selectin but are able to express all
other CAMs (52). The expression patterns of CAMs in
experimental models are in agreement with observations in human livers
(140, 145).
Selectins (137) and 2 integrins-ICAM-1
interactions (133, 156) are involved in neutrophil rolling
and adhesion, respectively, in postsinusoidal venules. Recently,
1 integrins, such as
4
1 have also been implicated in leukocyte rolling/adhesion
(37). However, evidence for transmigration from
postsinusoidal venules is limited (157), and the relevance
of this location for neutrophil migration into the parenchyma has been
questioned (20, 133). In contrast, sinusoids were
identified as the dominant sites for neutrophil extravasation
(20) (Fig. 2). However, multiple experimental approaches
could not establish a role of any adhesion molecule in neutrophil
accumulation in hepatic sinusoids (31, 35, 37, 66, 133, 156,
167). Thus it was repeatedly postulated that a combination of
factors, such as active vasoconstriction, vascular lining cell swelling
and injury, and reduced membrane flexibility after activation of the
neutrophil, contribute to the mechanical trapping of these leukocytes
in sinusoids (66, 72, 113). Neutrophil sequestration in
sinusoids may increase flow resistance but does not cause perfusion
failure and injury (21, 158). Extravasation is a
prerequisite for cell damage by neutrophils to occur (20).
For this process, the neutrophil requires
2 integrin-ICAM-1 (31) and
1 integrin-VCAM-1
(30) interactions. Engagement of these adhesion molecules
and E-selectin leads to further activation of the transmigrating
leukocyte (87). Once extravasated, the neutrophil uses, in
part, the
2 integrin lymphocyte function-associated
antigen-1 (LFA-1; CD11a/CD18) to adhere to ICAM-1 expressed on
hepatocytes (118). More importantly, engagement of the
2 integrin Mac-1 (CD11b/CD18) during neutrophil
adhesion to its target causes degranulation (protease release) and a
long-lasting, adhesion-dependent oxidant stress (107, 118,
141). During hepatic ischemia-reperfusion, ICAM-1 is
transcriptionally induced on hepatocytes and sinusoidal endothelial
cells (10, 35). However, the extensive vascular injury
during reperfusion (15, 36, 114) eliminates, in part, the
sinusoidal endothelial cell barrier and the neutrophil has direct
access to hepatocytes. This leaves the adherence to hepatocytes, which
is only partially dependent on LFA-1-ICAM-1 interactions
(118), as the only role for ICAM-1. As a consequence, ischemia-reperfusion injury is only moderately or not at all
attenuated by anti-ICAM-1 antibodies or in ICAM-1 gene knockout mice
(35, 124, 133, 156). In contrast, blocking neutrophil
transmigration with anti-ICAM-1 antibodies during endotoxemia prevented
the neutrophil-induced injury (31). For similar reasons,
blocking LFA-1 during endotoxemia was much more protective than the
same intervention in hepatic ischemia-reperfusion
(61). In contrast, blocking Mac-1 (CD11b) or the common
2 subunit CD18 was highly effective in preventing hepatic injury during ischemia-reperfusion (65,
101) and endotoxemia (68). In both cases,
antibodies functionally inactivated these neutrophils and prevented the
neutrophil-induced oxidant stress (65, 68), which led to a
significant reduction in injury.
The role of selectins in liver inflammation, in particular P-selectin, is controversial. Sinusoidal endothelial cells neither contain Weibel Palade bodies nor do they transcriptionally upregulate relevant levels of P-selectin (33). No selectin-dependent rolling of leukocytes has been observed in sinusoids (167). However, most neutrophils extravasate from sinusoids (20). Consistent with these findings, no protective effect was found in a model of neutrophil-mediated liver injury when P-selectin was blocked with antibodies or in gene knockout mice (33). In contrast, during ischemia-reperfusion, a number of interventions directed against selectins reduced hepatic neutrophil accumulation and cell injury (e.g., 3, 38, 108, 169). Because these findings cannot be explained by the prevention of P- or L-selectin-dependent rolling in sinusoids, alternative explanations must be considered. The severe vascular injury during reperfusion induces aggregation of platelets, which can adhere through a selectin-dependent mechanism (169). Neutrophils may adhere to platelets rather than endothelial cells through P-selectin. Kubes et al. (82) suggested recently that most liver ischemia-reperfusion models include some degree of intestinal ischemia, which leads to neutrophil accumulation in remote organs including the liver (49). Thus the lower number of neutrophils in the liver when selectins are blocked may be a secondary effect due to the protection of antiselectin therapy against intestinal reperfusion injury (82).
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NETWORK OF PRO- AND ANTI-INFLAMMATORY MEDIATORS |
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Complement.
Activation of complement is a critical event during reperfusion in
experimental animals (64) and humans (146)
(Figs. 1 and 2). The complement cascade can be rapidly activated by the extensive release of cellular proteins during the early reperfusion period. Complement factors, such as C5a, upregulate the
Mac-1 receptor on circulating neutrophils (166) and cause
neutrophil recruitment into sinusoids (7). C5a
primes and activates neutrophils and Kupffer cells for reactive oxygen
formation (64). However, complement activation has no
effect on NF-B activation and the expression of adhesion molecules
on endothelial cells and hepatocytes (7). In addition to
the proinflammatory effect, the assembled membrane attack complex can
directly cause cell injury. Evidence for complement deposition was
found in rat (19) as well as human livers
(139) during reperfusion. Thus blocking complement
activation effectively reduced the inflammatory response
(64), microcirculatory disturbances (90), and
cell injury (19, 64, 90).
Proinflammatory cytokines.
Primary cytokines, such as TNF- and IL-1, are generated mainly by
Kupffer cells (25, 148) but also by extrahepatic
macrophages (125) during reperfusion (Figs. 1 and 2). Both
TNF-
and IL-1 can upregulate Mac-1 (CD11b/CD18) on neutrophils and
recruit these cells into the liver vasculature (7, 166).
In addition, these cytokines recruit and activate CD4+
T-lymphocytes in the liver during the early reperfusion period (180). Resident (92) and newly accumulated
(180) CD4+ T-lymphocytes can produce
mediators, such as TNF-
, IFN-
, and granulocyte colony stimulating
factor, which amplify Kupffer cell activation and promote neutrophil
recruitment into the liver. In fact, CD4+
T-lymphocyte-deficient nude mice accumulate less neutrophils in the
postischemic liver and sustain less injury during the later reperfusion phase (180). Adoptive transfer of wild-type
T-cells into the nude mice restored neutrophil response and injury
during reperfusion (180). In a model of cold storage
and ex vivo, blood-free reperfusion, livers from nude mice
produced less TNF-
and IFN-
and had less injury
(92). These data suggest that resident CD4+ T
lymphocytes are activated during hepatic
ischemia-reperfusion. The fact that inactivation of Kupffer
cells with gadolinium chloride had similar effects indicates an
interaction and cross-activation between these cells (92).
However, despite the increased hepatic CD40 expression during
reperfusion, no effect on cytokine formation or injury was found in
livers from CD40-deficient mice (92). In contrast, recent
observations in a warm ischemia-reperfusion model indicate that
CD154-CD40 T-cell co-stimulation is important for injury and neutrophil
recruitment in vivo (142). These data are consistent with
previous reports (75, 85, 149), which described
reduced hepatic neutrophil infiltration and injury in animals treated
with T-cell-deactivating drugs, such as cyclosporine and FK506.
Together, these newer findings clearly demonstrate a key role for
CD4+ T-lymphocytes in cytokine formation, Kupffer cell
activation and hepatic neutrophil recruitment. In contrast to activated
complement factors, cytokines cause neutrophil sequestration in
sinusoids as well as adherence in postsinusoidal venules
(7). The latter effect is mediated by the transcriptional
upregulation of adhesion molecules on endothelial cells due to the
activation of the transcription factor NF-
B (10, 23, 31,
32). In addition, TNF-
and IL-1 are potent inducers of
hepatic CXC chemokine synthesis (24), and under certain
circumstances TNF-
can directly trigger apoptotic cell death
(91). Because of the central role of TNF-
in promoting the inflammatory response at different levels, suppressing the formation of TNF-
or neutralizing it with antibodies proved to be
highly effective in attenuating acute postischemic inflammation and injury (23, 25, 32). However, it must be considered that TNF-
is also involved in liver regeneration (1),
which is vital for the long-term recovery from the ischemic
insult and survival (16).
Chemokines.
Several studies demonstrated the importance of chemokines, especially
the neutrophil chemoattractant CXC chemokines MIP-2, KC, and
cytokine-induced neutrophil chemoattractant-1 (CINC-1), in hepatic
ischemia-reperfusion injury (24, 48, 94) (Figs. 1
and 2). Cytokines induce chemokine formation in Kupffer cells and
hepatocytes (24, 48). Because of their potent chemotactic activity for neutrophils, it is generally assumed that CXC chemokines recruit neutrophils into the postischemic liver. Transgenic
mice, which overexpress the human IL-8 gene, had neutrophil
accumulation in liver sinusoids without injury (143).
However, selective overexpression of CINC-1 in hepatocytes with a viral
vector induced a chemotactic gradient, which not only caused neutrophil
sequestration in sinusoids but also transmigration and injury
(105). The capacity to upregulate Mac-1 on neutrophils was
demonstrated for IL-8 (28) and MIP-2 (7) but
not for CINC-1 (176) and KC (7). Compared
with TNF-, IL-1, and complement factors, recombinant CXC chemokines proved to be not very potent systemic activators of neutrophils (7). Thus the capacity of CXC chemokines to recruit
neutrophils into sinusoids or even venules was limited compared
with the other mediators (7). This raises questions
regarding the actual mechanism of CXC chemokine involvement in a
complex pathophysiology, such as ischemia-reperfusion injury.
Lipid mediators.
Several lipid-derived inflammatory mediators have been implicated in
the pathophysiology of reperfusion injury (Figs. 1 and 2). Platelet
activating factor (PAF) is formed mainly by endothelial cells in
experimental models and in humans during ischemia-reperfusion (45, 177). PAF can prime neutrophils for generation of
superoxide (9). In addition, PAF is a potent activator of
the 2 integrin Mac-1 and of adherence-dependent reactive
oxygen formation (141). PAF receptor antagonists protected
against reperfusion injury (150, 177). The beneficial
effect is, at least in part, due to reduced neutrophil activation and
reduced microvascular damage (159). Leukotriene
B4 (LTB4) is a potent chemotactic factor for human neutrophils (138). It is generated in large
quantities presumably by neutrophils during the neutrophil-induced
injury phase after hepatic ischemia (51). As such,
it may contribute to the amplification of the neutrophil response
during reperfusion (51). Lipid peroxidation products are
chemotactic factors for neutrophils (27). This mechanism
may be responsible for the propagation of the inflammatory injury
during reperfusion especially at times when many peptide mediators are
no longer generated (102). Lipid-soluble antioxidants and
iron chelators can reduce the inflammatory response and reperfusion
injury by reducing the signal (lipid peroxidation products) for
continued neutrophil recruitment (55, 102).
Anti-inflammatory cytokines.
Inflammation is a complex process, which requires not only mediators
that promote but others that downregulate the inflammatory response
(Fig. 1). IL-6 is formed during reperfusion after hepatic ischemia (16, 111). Reperfusion injury can be
attenuated by the administration of recombinant IL-6 or is aggravated
in IL-6-deficient mice (16). IL-6 is thought to act
through several different mechanisms. IL-6 can downregulate TNF-
mRNA during reperfusion, and it promotes hepatocyte regeneration
(16). The administration of IL-10 to rats after liver
transplantation reduced formation of CXC chemokines and improved
reperfusion injury and survival (179). The protective
effect of IL-10 may be related to its ability to suppress the
transcriptional activation of TNF formation, which may be responsible
for the subsequent effects, such as reduced chemokine formation,
reduced accumulation of neutrophils, and less ICAM-1 expression
(173). A similar anti-inflammatory mechanism was described
for IL-13, which attenuates reperfusion injury (174). The
difference between IL-10 and IL-13 appears to be that IL-10 prevents
activation of NF-
B and IL-13 activates the transcription factor
STAT-6 (174). Secretory leukocyte protease inhibitor
(SLPI) is a protein that can reduce TNF formation by macrophages
(74) and can inhibit serine proteases including proteases
released by neutrophils (e.g., elastase, cathepsin G, etc.)
(153). Recently, Lentsch et al. (96)
demonstrated that SLPI protected against reperfusion injury by reducing
TNF formation and attenuation of the TNF-dependent inflammatory
response. In contrast to IL-6, IL-10, IL-13, and SLPI, IL-12 appears to
be supporting the inflammatory response and postischemic injury
(95). Studies with neutralizing anti-IL-12 antibodies or
with IL-12-deficient mice showed that IL-12 formation is important for
prolonged TNF-
and IFN-
formation, both of which promote a
neutrophil-dependent injury mechanism during reperfusion
(95). Thus a complex network of regulatory cytokines and
other mediators modulates the inflammatory response after hepatic
ischemia (Figs. 1 and 2).
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MODE OF CELL DEATH DURING ISCHEMIA-REPERFUSION |
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Comments regarding this controversial topic will be limited. For an in-depth discussion, the reader is referred to a more specialized review (57). During reperfusion, cells are killed by a combination of several mechanisms including intracellular oxidant stress, exposure to external cytotoxic mediators, and prolonged ischemia. Cell death of hepatocytes and endothelial cells during reperfusion is characterized by swelling of cells and their organelles, release of cell contents, eosinophilia, karyolysis, and induction of inflammation (43). These morphological features are characteristic for oncotic necrosis. However, in recent years it was postulated that most liver cells actually die by apoptosis (26, 80), which is morphologically characterized by cell shrinkage, formation of apoptotic bodies with intact cell organelles, and the absence of inflammation (106). On the basis of the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay, it was suggested that 50-80% of all liver endothelial cells and hepatocytes die through apoptosis during the first 3-6 h of reperfusion (26, 80). However, on closer scrutiny of these data, a number of serious concerns emerged. First, the TUNEL assay alone is not suitable to identify apoptosis, because DNA strand breaks also occur during oncotic necrosis (57). Second, the minimal amount of caspase activation does not correlate with the alleged large number of apoptotic cells (43, 57). Third, immediate cell contents release and inflammation are not consistent with apoptosis as the only mode of cell death (43, 57). Fourth, interventions such as overexpression of Bcl-2 can prevent both apoptotic and necrotic cell death (57). Fifth, on the basis of morphological criteria, the number of apoptotic cells never exceeds 1-2% of all endothelial cells and hepatocytes at any time during reperfusion after 60 min of warm ischemia (43). Similar observations were made after cold storage and reperfusion (131). Thus even if the turnover of apoptotic cells is considered, >90% of cells die by oncotic necrosis during ischemia-reperfusion. In contrast to previous assumptions that apoptosis does not cause inflammation, we demonstrated that apoptotic cell death can trigger neutrophil transmigration with massive aggravation of the apoptotic cell injury (69). This mechanism may explain why caspase inhibitors can have a significant overall protective effect on hepatic ischemia-reperfusion injury (78).
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HEAT SHOCK AND ISCHEMIC PRECONDITIONING |
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Heat shock (i.e., increasing the body temperature to 42°C for 15 min) or ischemic preconditioning [i.e., exposure of the liver to a brief period of ischemia (5-10 min)] and reperfusion
effectively protect the liver against warm ischemia (84,
104) and cold storage injury (170). Preliminary
studies in humans confirmed the efficacy of ischemic
preconditioning (22). There is strong evidence that
adenosine is a key mediator in ischemic preconditioning (128). Adenosine stimulates the adenosine A2
receptor (5, 120, 129), which initiates NO formation
(128, 129), and causes activation of protein kinase
C, adenosine monophosphate-activated protein kinase, and p38 MAPK
(17, 18, 127, 151). Activation of these intracellular
signaling pathways not only triggers increased tolerance of the
hepatocytes and endothelial cells against ischemic insults but
also causes quiesent cells to enter the cell cycle and initiate a
regenerative response (151). Stimulation of regeneration with recombinant IL-6 was shown to attenuate reperfusion injury after
warm ischemia (16). Induction of heat shock
proteins (HSP), especially HSP70 (84) and heme oxygenase-1
(HSP32) (2, 131), has also been implicated in the
mechanism of preconditioning. HSP induction can reduce the nuclear
binding of proinflammatory transcription factors (154) and
increase the antioxidant capacity of cells (8). Both
effects may contribute to the reduced formation of TNF- and an
attenuated inflammatory response in preconditioned livers
(6, 172). In addition, carbon monoxide, a by-product of
heme oxygenase-1 activity, was shown to activate p38 MAPK as a key
mechanism of carbon monoxide-mediated protection against ischemia-reperfusion injury (4). Thus a
combination of factors may contribute to the reduced injury and the
improved long-term survival in animals subjected to preconditioning
including the increased tolerance to ischemic injury and
oxidant stress, a reduced inflammatory response, and enhanced regeneration.
In summary, ischemia-reperfusion injury is a complex pathophysiology with a number of contributing factors (Figs. 1 and 2). The ischemic insult can lead to sublethal cell injury, which is aggravated by the formation of reactive oxygen from various intracellular sources during reperfusion. In addition, formation of proinflammatory mediators and the recruitment and activation of macrophages, neutrophils, and lymphocytes can further enhance the injury. Microcirculatory disturbances lead to underperfused areas in the liver and may cause ischemic injury. All mechanisms contribute to various degrees in the overall pathophysiology. Therefore, it is difficult to achieve effective protection by targeting individual mediators or mechanisms. In contrast, the most promising protective strategy against ischemia-reperfusion injury explored during the last few years is preconditioning, which appears to increase the resistance of liver cells to ischemia and reperfusion events. Preconditioning or pharmacological interventions that mimic these effects have the greatest potential to improve clinical outcome in liver transplantation and liver surgery with vascular exclusion.
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FOOTNOTES |
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Address for reprint requests and other correspondence: H. Jaeschke, Liver Research Institute, Univ. of Arizona, AHSC 245136, 1501 N. Campbell Ave. Tucson, AZ 85724.
10.1152/ajpgi.00342.2002
Received 14 August 2002; accepted in final form 10 September 2002.
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