INVITED REVIEW
Molecular mechanisms of hepatic ischemia-reperfusion injury and preconditioning

Hartmut Jaeschke

Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205


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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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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).


    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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Fig. 1.   Liver injury mechanisms and the initiation of the inflammatory response with recruitment of neutrophils during the initial reperfusion phase after hepatic ischemia. EC, endothelial cells; CAM, cellular adhesion molecules; PMN, polymorphonuclear leukocyte neutrophil; ROS, reactive oxygen species; TNF, TNF-alpha or -beta ; GM-CSF, granulocyte macrophage colony stimulating factor; PAF, platelet activating factor; CXC, CXC chemokine (e.g., IL-8, KC, MIP-2, CINC-1); C5a, activated complement factor; SLP, secretory leukocyte protease inhibitor.

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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Fig. 2.   Liver injury during the later, neutrophil-dominated injury phase after hepatic ischemia. LPO, lipid peroxidation products; LTB4, leukotriene B4.

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-kappa B and activator protein-1 (AP-1) (34, 56). The postischemic oxidant stress can enhance the expression of genes, such as TNF-alpha , 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-kappa B and AP-1 activation (8, 32, 70, 132, 181).


    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).


    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 beta 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 beta 2 integrins-ICAM-1 interactions (133, 156) are involved in neutrophil rolling and adhesion, respectively, in postsinusoidal venules. Recently, beta 1 integrins, such as alpha 4beta 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 beta 2 integrin-ICAM-1 (31) and beta 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 beta 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 beta 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 beta 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).


    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-kappa 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-alpha 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-alpha 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-beta , IFN-gamma , 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-alpha and IFN-gamma 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-kappa B (10, 23, 31, 32). In addition, TNF-alpha and IL-1 are potent inducers of hepatic CXC chemokine synthesis (24), and under certain circumstances TNF-alpha can directly trigger apoptotic cell death (91). Because of the central role of TNF-alpha in promoting the inflammatory response at different levels, suppressing the formation of TNF-alpha 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-alpha 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-alpha , 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 beta 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-alpha 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-kappa 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-alpha and IFN-gamma 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).


    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).


    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-alpha 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.


    FOOTNOTES

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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1.   Akerman, P, Cote P, Yang SQ, McClain C, Nelson S, Bagby GJ, and Diehl AM. Antibodies to tumor necrosis factor-alpha inhibit liver regeneration after partial hepatectomy. Am J Physiol Gastrointest Liver Physiol 263: G579-G585, 1992[Abstract/Free Full Text].

2.   Amersi, F, Buelow R, Kato H, Ke B, Coito AJ, Shen XD, Zhao D, Zaky J, Melinek J, Lassman CR, Kolls JK, Alam J, Ritter T, Volk HD, Farmer DG, Ghobrial RM, Busuttil RW, and Kupiec-Weglinski JW. Upregulation of heme oxygenase-1 protects genetically fat Zucker rat livers from ischemia/reperfusion injury. J Clin Invest 104: 1631-1639, 1999[Abstract/Free Full Text].

3.   Amersi, F, Dulkanchainun T, Nelson SK, Farmer DG, Kato H, Zaky J, Melinek J, Shaw GD, Kupiec-Weglinski JW, Horwitz LD, Horwitz MA, and Busuttil RW. A novel iron chelator in combination with a P-selectin antagonist prevents ischemia/reperfusion injury in a rat liver model. Transplantation 71: 112-118, 2001[ISI][Medline].

4.   Amersi, F, Shen XD, Anselmo D, Melinek J, Iyer S, Southard DJ, Katori M, Volk HD, Busuttil RW, Buelow R, and Kupiec-Weglinski JW. Ex vivo exposure to carbon monoxide prevents hepatic ischemia/reperfusion injury through p38 MAP kinase pathway. Hepatology 35: 815-823, 2002[ISI][Medline].

5.   Arai, M, Thurman RG, and Lemasters JJ. Contribution of adenosine A(2) receptors and cyclic adenosine monophosphate to protective ischemic preconditioning of sinusoidal endothelial cells against storage/reperfusion injury in rat livers. Hepatology 32: 297-302, 2000[ISI][Medline].

6.   Arai, M, Thurman RG, and Lemasters JJ. Ischemic preconditioning of rat livers against cold storage-reperfusion injury: role of nonparenchymal cells and the phenomenon of heterologous preconditioning. Liver Transpl 7: 292-299, 2001[ISI][Medline].

7.   Bajt, ML, Farhood A, and Jaeschke H. Effects of CXC chemokines on neutrophil activation and sequestration in the hepatic vasculature. Am J Physiol Gastrointest Liver Physiol 281: G1188-G1195, 2001[Abstract/Free Full Text].

8.   Bauer, M, and Bauer I. Heme oxygenase-1: redox regulation and role in the hepatic response to oxidative stress. Antiox Redox Signal 4: 749-758, 2002[ISI][Medline].

9.   Bautista, AP, and Spitzer JJ. Platelet activating factor stimulates and primes the liver, Kupffer cells and neutrophils to release superoxide anion. Free Radic Res Commun 17: 195-209, 1992[ISI][Medline].

10.   Bell, FP, Essani NA, Manning AM, and Jaeschke H. Ischemia-reperfusion activates the nuclear transcription factor NF-kappa B and upregulates messenger RNA synthesis of adhesion molecules in the liver in vivo. Hepatol Res 8: 178-188, 1997[ISI].

11.   Bilzer, M, and Gerbes A. Preservation injury of the liver: Mechanisms and novel therapeutic strategies. J Hepatol 32: 508-515, 2000[ISI][Medline].

12.   Bilzer, M, Jaeschke H, Vollmar AM, Paumgartner G, and Gerbes AL. Prevention of Kupffer cell-induced injury in rat liver by atrial natriuretic peptide (ANP): A novel endogenous defense mechanism against oxidant injury. Am J Physiol Gastrointest Liver Physiol 276: G1137-G1144, 1999[Abstract/Free Full Text].

13.   Bilzer, M, and Lauterburg BH. Oxidant stress and potentiation of ischemia-reperfusion injury to the perfused rat liver by human polymorphonuclear leukocytes. J Hepatol 20: 473-477, 1994[ISI][Medline].

14.   Bilzer, M, Paumgartner G, and Gerbes AL. Glutathione protects the rat liver against reperfusion injury after hypothermic preservation. Gastroenterology 117: 200-210, 1999[ISI][Medline].

15.   Caldwell-Kenkel, JC, Currin RT, Tanaka Y, Thurman RG, and Lemasters JJ. Kupffer cell activation and endothelial cell damage after storage of rat livers: effects of reperfusion. Hepatology 13: 83-95, 1991[ISI][Medline].

16.   Camargo, CA, Jr, Madden JF, Gao W, Selvan RS, and Clavien PA. Interleukin-6 protects liver against warm ischemia/reperfusion injury and promotes hepatocyte proliferation in the rodent. Hepatology 26: 1513-1520, 1997[ISI][Medline].

17.   Carini, R, De Cesaris MG, Splendore R, Vay D, Domenicotti C, Nitti MP, Paola D, Pronzato MA, and Albano E. Signal pathway involved in the development of hypoxic preconditioning in rat hepatocytes. Hepatology 33: 131-139, 2001[ISI][Medline].

18.   Carini, R, Grazia De Cesaris M, Splendore R, and Albano E. Stimulation of p38 MAP kinase reduces acidosis and Na(+) overload in preconditioned hepatocytes. FEBS Lett 491: 180-183, 2000[ISI].

19.   Chavez-Cartaya, RE, DeSola GP, Wright L, Jamieson NV, and White DJ. Regulation of the complement cascade by soluble complement receptor type 1. Protective effect in experimental liver ischemia and reperfusion. Transplantation 59: 1047-1052, 1995[ISI][Medline].

20.   Chosay, JG, Essani NA, Dunn CJ, and Jaeschke H. Neutrophil margination and extravasation in sinusoids and venules of the liver during endotoxin-induced injury. Am J Physiol Gastrointest Liver Physiol 272: G1195-G1200, 1997[Abstract/Free Full Text].

21.   Chun, K, Zhang J, Biewer J, Ferguson D, and Clemens MG. Microcirculatory failure determines lethal hepatocyte injury in ischemic/reperfused rat livers. Shock 1: 3-9, 1994[ISI][Medline].

22.   Clavien, PA, Yadav S, Sindram D, and Bentley RC. Protective effects of ischemic preconditioning for liver resection performed under inflow occlusion in humans. Ann Surg 232: 155-162, 2000[ISI][Medline].

23.   Colletti, LM, Cortis A, Lukacs N, Kunkel SL, Green M, and Strieter RM. Tumor necrosis factor up-regulates intercellular adhesion molecule 1, which is important in the neutrophil-dependent lung and liver injury associated with hepatic ischemia and reperfusion in the rat. Shock 10: 182-191, 1998[ISI][Medline].

24.   Colletti, LM, Kunkel SL, Walz A, Burdick MD, Kunkel RG, Wilke CA, and Strieter RM. The role of cytokine networks in the local liver injury following hepatic ischemia/reperfusion in the rat. Hepatology 23: 506-514, 1996[ISI][Medline].

25.   Colletti, LM, Remick DG, Burtch GD, Kunkel SL, Strieter RM, and Campbell DA, Jr. Role of tumor necrosis factor-alpha in the pathophysiologic alterations after hepatic ischemia/reperfusion injury in the rat. J Clin Invest 85: 1936-1943, 1990[ISI][Medline].

26.   Cursio, R, Gugenheim J, Ricci JE, Crenesse D, Rostagno P, Maulon L, Saint-Paul MC, Ferrua B, and Auberger AP. A caspase inhibitor fully protects rats against lethal normothermic liver ischemia by inhibition of liver apoptosis. FASEB J 13: 253-261, 1999[Abstract/Free Full Text].

27.   Curzio, M, Esterbauer H, Di Mauro C, Cecchini G, and Dianzani MU. Chemotactic activity of the lipid peroxidation product 4-hydroxynonenal and homologous hydroxyalkenals. Biol Chem Hoppe Seyler 367: 321-329, 1986[ISI][Medline].

28.   Detmers, PA, Lo SK, Olsen-Egbert E, Walz A, Baggiolini M, and Cohn ZA. Neutrophil-activating protein 1/interleukin 8 stimulates the binding activity of the leukocyte adhesion receptor CD11b/CD18 on human neutrophils. J Exp Med 171: 1155-1162, 1990[Abstract].

29.   Elimadi, A, Sapena R, Settaf A, Le Louet H, Tillement J, and Morin D. Attenuation of liver normothermic ischemia-reperfusion injury by preservation of mitochondrial functions with S-15176, a potent trimetazidine derivative. Biochem Pharmacol 62: 509-516, 2001[ISI][Medline].

30.   Essani, NA, Bajt ML, Vonderfecht SL, Farhood A, and Jaeschke H. Transcriptional activation of vascular cell adhesion molecule-1 (VCAM-1) gene in vivo and its role in the pathophysiology of neutrophil-induced liver injury in murine endotoxin shock. J Immunol 158: 5941-5948, 1997[Abstract].

31.   Essani, NA, Fisher MA, Farhood A, Manning AM, Smith CW, and Jaeschke H. Cytokine-induced hepatic intercellular adhesion molecule-1 (ICAM-1) mRNA expression and its role in the pathophysiology of murine endotoxin shock and acute liver failure. Hepatology 21: 1632-1639, 1995[ISI][Medline].

32.   Essani, NA, Fisher MA, and Jaeschke H. Inhibition of NF-kappa B by dimethyl sulfoxide correlates with suppression of TNF-alpha formation, reduced ICAM-1 gene transcription, and protection against endotoxin-induced liver injury. Shock 7: 90-96, 1997[ISI][Medline].

33.   Essani, NA, Fisher MA, Simmons CA, Hoover JL, Farhood A, and Jaeschke H. Increased P-selectin gene expression in the liver vasculature and its role in the pathophysiology of neutrophil-induced liver injury in murine endotoxin shock. J Leukoc Biol 63: 288-296, 1998[Abstract].

34.   Fan, C, Zwacka RM, and Engelhardt JF. Therapeutic approaches for ischemia/reperfusion injury in the liver. J Mol Med 77: 577-592, 1999[ISI][Medline].

35.   Farhood, A, McGuire GM, Manning AM, Miyasaka M, Smith CW, and Jaeschke H. Intercellular adhesion molecule-1 (ICAM-1) gene expression and its role in neutrophil-induced ischemia-reperfusion injury in the liver. J Leukoc Biol 57: 368-374, 1995[Abstract].

36.   Fisher, MA, Eversole RR, Beuving LJ, and Jaeschke H. Sinusoidal endothelial cell and parenchymal cell injury during endotoxemia and hepatic ischemia-reperfusion: protection by the 21-aminosteroid tirilazad mesylate. Int Hepatol Commun 6: 121-129, 1997[ISI].

37.   Fox-Robichaud, A, and Kubes P. Molecular mechanisms of tumor necrosis factor alpha -stimulated leukocyte recruitment into the murine hepatic circulation. Hepatology 31: 1123-1127, 2000[ISI][Medline].

38.   Garcia-Criado, FJ, Toledo-Pereyra LH, Lopez-Neblina F, Phillips ML, Paez-Rollys A, and Misawa K. Role of P-selectin in total hepatic ischemia and reperfusion. J Am Coll Surg 181: 327-334, 1995[ISI][Medline].

39.   Gonzalez-Flecha, B, Cutrin JC, and Boveris A. Time course and mechanism of oxidative stress and tissue damage in rat liver subjected to in vivo ischemia-reperfusion. J Clin Invest 91: 456-464, 1993[ISI][Medline].

40.   Goto, M, Takei Y, Kawano S, Nagano K, Tsuji S, Masuda E, Nishimura Y, Okumura S, Kashiwagi T, Fusamoto H, and Kamada T. Endothelin-1 involved in the pathogenesis of ischemia/reperfusion liver injury by hepatic microcirculatory disturbances. Hepatology 19: 675-681, 1994[ISI][Medline].

41.   Granger, DN, and Kubes P. The microcirculation and inflammation: modulation of leukocyte-endothelial cell adhesion. J Leukoc Biol 55: 662-675, 1994[Abstract].

42.   Grattagliano, I, Vendemiale G, and Lauterburg BH. Reperfusion injury of the liver: role of mitochondria and protection by glutathione ester. J Surg Res 86: 2-8, 1999[ISI][Medline].

43.   Gujral, JS, Bucci TJ, Farhood A, and Jaeschke H. Mechanism of cell death during warm hepatic ischemia-reperfusion in rats: apoptosis or necrosis? Hepatology 33: 397-405, 2001[ISI][Medline].

44.   Harbrecht, BG, Wu B, Watkins SC, Marshall HP, Jr, Peitzman AB, and Billiar TR. Inhibition of nitric oxide synthase during hemorrhagic shock increases hepatic injury. Shock 4: 332-337, 1995[ISI][Medline].

45.   Hashikura, Y, Kawasaki S, Matsunami H, Ikegami T, and Makuuchi M. Intraoperative increment of platelet-activating factor in clinical liver transplantation. Clin Transplant 8: 27-29, 1994[ISI][Medline].

46.   Hines, IN, Harada H, Bharwani S, Pavlick KP, Hoffman JM, and Grisham MB. Enhanced post-ischemic liver injury in iNOS-deficient mice: a cautionary note. Biochem Biophys Res Commun 284: 972-976, 2001[ISI][Medline].

47.   Hines, IN, Kawachi S, Harada H, Pavlick KP, Hoffman JM, Bharwani S, Wolf RE, and Grisham MB. Role of nitric oxide in liver ischemia and reperfusion injury. Mol Cell Biochem 234-235: 229-237, 2002[ISI].

48.   Hisama, N, Yamaguchi Y, Ishiko T, Miyanari N, Ichiguchi O, Goto M, Mori K, Watanabe K, Kawamura K, Tsurufuji S, and Ogawa M. Kupffer cell production of cytokine-induced neutrophil chemoattractant following ischemia/reperfusion injury in rats. Hepatology 24: 1193-1198, 1996[ISI][Medline].

49.   Horie, Y, Wolf R, Miyasaka M, Anderson DC, and Granger DN. Leukocyte adhesion and hepatic microvascular responses to intestinal ischemia/reperfusion in rats. Gastroenterology 111: 666-673, 1996[ISI][Medline].

50.   Hsu, CM, Wang JS, Liu CH, and Chen LW. Kupffer cells protect liver from ischemia-reperfusion injury by an inducible nitric oxide synthase-dependent mechanism. Shock 17: 280-285, 2002[ISI][Medline].

51.   Hughes, H, Farhood A, and Jaeschke H. The role of leukotriene B4 in the pathogenesis of hepatic ischemia-reperfusion injury in the rat. Prostaglandins Leukot Essent Fatty Acids 45: 113-119, 1992[ISI][Medline].

52.   Jaeschke, H. Cellular adhesion molecules: regulation and functional significance in the pathogenesis of liver diseases. Am J Physiol Gastrointest Liver Physiol 273: G602-G611, 1997[Abstract/Free Full Text].

53.   Jaeschke, H. Mechanism of reperfusion injury after warm ischemia of the liver. J Hepatol 21: 402-408, 1998.

54.   Jaeschke, H. Preservation injury: mechanisms, prevention and consequences. J Hepatol 25: 774-780, 1996[ISI][Medline].

55.   Jaeschke, H. Reactive oxygen and ischemia-reperfusion injury of the liver. Chem Biol Interact 79: 115-136, 1991[ISI][Medline].

56.   Jaeschke, H. Reactive oxygen and mechanisms of inflammatory liver injury. J Gastroenterol Hepatol 15: 718-724, 2000[ISI][Medline].

57.  Jaeschke H. Reperfusion injury after warm ischemia or cold storage of the liver: role of apoptotic cell death. Transplant Proc. In press.

58.   Jaeschke, H. Vascular oxidant stress and hepatic ischemia-reperfusion injury. Free Radic Res Commun 12-13: 737-743, 1991.

59.   Jaeschke, H, Bautista AP, Spolarics Z, and Spitzer JJ. Superoxide generation by Kupffer cells and priming of neutrophils during reperfusion after hepatic ischemia. Free Radic Res Commun 15: 277-284, 1991[ISI][Medline].

60.   Jaeschke, H, Bautista AP, Spolarics Z, and Spitzer JJ. Superoxide generation by neutrophils and Kupffer cells during in vivo reperfusion after hepatic ischemia in rats. J Leukoc Biol 52: 377-382, 1992[Abstract].

61.   Jaeschke, H, Essani NA, Farhood A, and Smith CW. Mechanisms of inflammatory liver injury during ischemia-reperfusion and endotoxemia. In: Cells of the Hepatic Sinusoid. Proceedings of the Eighth International Symposium on Cells of the Hepatic Sinusoid, edited by Wisse E, Knook DL, and Balabaud C.. Leiden, The Netherlands: Kupffer Cell Foundation, 1997, vol. 6, p. 158-163.

62.   Jaeschke, H, and Farhood A. Kupffer cell activation after no-flow ischemia versus hemorrhagic shock. Free Radic Biol Med 33: 210-219, 2002[ISI][Medline].

63.   Jaeschke, H, and Farhood A. Neutrophil and Kupffer cell-induced oxidant stress and ischemia-reperfusion injury in rat liver in vivo. Am J Physiol Gastrointest Liver Physiol 260: G355-G362, 1991[Abstract/Free Full Text].

64.   Jaeschke, H, Farhood A, Bautista AP, Spolarics Z, and Spitzer JJ. Complement activates Kupffer cells and neutrophils during reperfusion after hepatic ischemia. Am J Physiol Gastrointest Liver Physiol 264: G801-G809, 1993[Abstract/Free Full Text].

65.   Jaeschke, H, Farhood A, Bautista AP, Spolarics Z, Spitzer JJ, and Smith CW. Functional inactivation of neutrophils with a Mac-1 (CD11b/CD18) monoclonal antibody protects against ischemia-reperfusion injury in rat liver. Hepatology 17: 915-923, 1993[ISI][Medline].

66.   Jaeschke, H, Farhood A, Fisher MA, and Smith CW. Sequestration of neutrophils in the hepatic vasculature during endotoxemia is independent of beta 2 integrins and intercellular adhesion molecule-1. Shock 6: 345-350, 1996[ISI][Medline].

67.   Jaeschke, H, Farhood A, and Smith CW. Neutrophils contribute to ischemia-reperfusion injury in rat liver in vivo. FASEB J 4: 3355-3359, 1990[Abstract/Free Full Text].

68.   Jaeschke, H, Farhood A, and Smith CW. Neutrophil-induced liver cell injury in endotoxin shock is a CD11b/CD18-dependent mechanism. Am J Physiol Gastrointest Liver Physiol 261: G1051-G1056, 1991[Abstract/Free Full Text].

69.   Jaeschke, H, Fisher MA, Lawson JA, Simmons CA, Farhood A, and Jones DA. Activation of caspase 3 (CPP32)-like proteases is essential for TNF-alpha-induced hepatic parenchymal cell apoptosis and neutrophil-mediated necrosis in a murine endotoxin shock model. J Immunol 160: 3480-3486, 1998[Abstract/Free Full Text].

70.   Jaeschke, H, Ho YS, Fisher MA, Lawson JA, and Farhood A. Glutathione peroxidase deficient mice are more susceptible to neutrophil-mediated hepatic parenchymal cell injury during endotoxemia: importance of an intracellular oxidant stress. Hepatology 29: 443-450, 1999[ISI][Medline].

71.   Jaeschke, H, and Mitchell JR. Mitochondria and xanthine oxidase both generate reactive oxygen species after hypoxic damage in isolated perfused rat liver. Biochem Biophys Res Commun 160: 140-147, 1989[ISI][Medline].

72.   Jaeschke, H, and Smith CW. Mechanisms of neutrophil-induced parenchymal cell injury. J Leukoc Biol 61: 647-653, 1997[Abstract].

73.   Jassem, W, Fuggle SV, Rela M, Koo DD, and Heaton ND. The role of mitochondria in ischemia/reperfusion injury. Transplantation 73: 493-499, 2002[ISI][Medline].

74.   Jin, FY, Nathan C, Radzioch D, and Ding A. Secretory leukocyte protease inhibitor: a macrophage product induced by and antagonistic to bacterial lipopolysaccharide. Cell 88: 417-426, 1997[ISI][Medline].

75.   Kawano, K, Kim YI, Ono M, Goto S, Kai T, and Kobayashi M. Evidence that both cyclosporin and azathioprine prevent warm ischemia reperfusion injury to the rat liver. Transpl Int 6: 330-336, 1993[ISI][Medline].

76.   Kim, YI, Hwang YJ, Song KE, Yun YK, Lee JW, and Chun BY. Hepatocyte protection by a protease inhibitor against ischemia/reperfusion injury of human liver. J Am Coll Surg 195: 41-50, 2002[ISI][Medline].

77.  Knight TR, Ho YS, Farhood A, and Jaeschke H. Peroxynitrite is a critical mediator of acetaminophen hepatotoxicity in murine livers: protection by glutathione. J Pharmacol Exp Therap. In press.

78.   Kobayashi, A, Imamura H, Isobe M, Matsuyama Y, Soeda J, Matsunaga K, and Kawasaki S. Mac-1 (CD11b/CD18) and intercellular adhesion molecule-1 in ischemia-reperfusion injury of rat liver. Am J Physiol Gastrointest Liver Physiol 281: G577-G585, 2001[Abstract/Free Full Text].

79.   Koeppel, TA, Kraus T, Thies JC, Gebhard MM, Otto G, and Post S. Effects of mixed ETA and ETB-receptor antagonist (Ro-47-0203) on hepatic microcirculation after warm ischemia. Dig Dis Sci 42: 1316-1321, 1997[ISI][Medline].

80.   Kohli, V, Selzner M, Madden JF, Bentley RC, and Clavien PA. Endothelial cell and hepatocyte deaths occur by apoptosis after ischemia-reperfusion injury in the rat liver. Transplantation 67: 1099-1105, 1999[ISI][Medline].

81.   Koo, A, Komatsu H, Tao G, Inoue M, Guth PH, and Kaplowitz N. Contribution of no-reflow phenomenon to hepatic injury after ischemia-reperfusion: evidence for a role for superoxide anion. Hepatology 15: 507-514, 1991[ISI].

82.   Kubes, P, Payne D, and Woodman RC. Molecular mechanisms of leukocyte recruitment in postischemic liver microcirculation. Am J Physiol Gastrointest Liver Physiol 283: G139-G147, 2002[Abstract/Free Full Text].

83.   Kumamoto, Y, Suematsu M, Shimazu M, Kato Y, Sano T, Makino N, Hirano KI, Naito M, Wakabayashi G, Ishimura Y, and Kitajima M. Kupffer cell-independent acute hepatocellular oxidative stress and decreased bile formation in post-cold-ischemic rat liver. Hepatology 30: 1454-1463, 1999[ISI][Medline].

84.   Kume, M, Yamamoto Y, Saad S, Gomi T, Kimoto S, Shimabukuro T, Yagi T, Nakagami M, Takada Y, Morimoto T, and Yamaoka Y. Ischemic preconditioning of the liver in rats: implications of heat shock protein induction to increase tolerance of ischemia-reperfusion injury. J Lab Clin Med 128: 251-258, 1996[ISI][Medline].

85.   Kurokawa, T, Kobayashi H, Nonami T, Harada A, Nakao A, Sugiyama S, Ozawa T, and Takagi H. Beneficial effects of cyclosporine on postischemic liver injury in rats. Transplantation 53: 308-311, 1992[ISI][Medline].

86.   Kushimoto, S, Okajima K, Uchiba M, Murakami K, Harada N, Okabe H, and Takatsuki K. Role of granulocyte elastase in ischemia/reperfusion injury of rat liver. Crit Care Med 24: 1908-1912, 1996[ISI][Medline].

87.   Lawson, JA, Burns AR, Farhood A, Bajt ML, Collins RG, Smith CW, and Jaeschke H. Pathophysiological importance of E- and L-selectin for neutrophil-induced liver injury during endotoxemia in mice. Hepatology 32: 990-998, 2000[ISI][Medline].

88.   Leducq, N, Delmas-Beauvieux MC, Bourdel-Marchasson I, Dufour S, Gallis JL, Canioni P, and Diolez P. Mitochondrial and energetic dysfunctions of the liver during normothermic reperfusion: protective effect of cyclosporine and role of the mitochondrial permeability transition pore. Transplant Proc 32: 479-480, 2000[ISI][Medline].

89.   Lee, VG, Johnson ML, Baust J, Laubach VE, Watkins SC, and Billiar TR. The roles of iNOS in liver ischemia-reperfusion injury. Shock 16: 355-360, 2001[ISI][Medline].

90.   Lehmann, TG, Koeppel TA, Munch S, Heger M, Kirschfink M, Klar E, and Post S. Impact of inhibition of complement by sCR1 on hepatic microcirculation after warm ischemia. Microvasc Res 62: 284-292, 2001[ISI][Medline].

91.   Leist, M, Gantner F, Bohlinger I, Germann PG, Tiegs G, and Wendel A. Murine hepatocyte apoptosis induced in vitro and in vivo by TNF-alpha requires transcriptional arrest. J Immunol 153: 1778-1788, 1994[Abstract/Free Full Text].

92.   Le Moine, O, Louis H, Demols A, Desalle F, Demoor F, Quertinmont E, Goldman M, and Deviere J. Cold liver ischemia-reperfusion injury critically depends on liver T cells and is improved by donor pretreatment with interleukin-10 in mice. Hepatology 31: 1266-1274, 2000[ISI][Medline].

93.   Lentsch, AB, Kato A, Yoshidome H, McMasters KM, and Edwards MJ. Inflammatory mechanisms and therapeutic strategies for warm hepatic ischemia/reperfusion injury. Hepatology 32: 169-173, 2000[ISI][Medline].

94.   Lentsch, AB, Yoshidome H, Cheadle WG, Miller FN, and Edwards MJ. Chemokine involvement in hepatic ischemia/reperfusion injury in mice: roles for macrophage inflammatory protein-2 and KC. Hepatology 27: 507-512, 1998[ISI][Medline].

95.   Lentsch, AB, Yoshidome H, Kato A, Warner RL, Cheadle WG, Ward PA, and Edwards MJ. Requirement for interleukin-12 in the pathogenesis of warm hepatic ischemia/ reperfusion injury in mice. Hepatology 30: 1448-1453, 1999[ISI][Medline].

96.   Lentsch, AB, Yoshidome H, Warner RL, Ward PA, and Edwards MJ. Secretory leukocyte protease inhibitor in mice regulates local and remote organ inflammatory injury induced by hepatic ischemia/reperfusion. Gastroenterology 117: 953-961, 1999[ISI][Medline].

97.   Li, JM, and Shah AM. Differential NADPH- versus NADH-dependent superoxide production by phagocyte-type endothelial cell NADPH oxidase. Cardiovasc Res 52: 477-486, 2001[ISI][Medline].

98.   Li, XK, Matin AFM, Suzuki H, Uno T, Yamaguchi T, and Harada Y. Effect of protease inhibitor on ischemia-reperfusion injury of the rat liver. Transplantation 56: 1331-1336, 1993[ISI][Medline].

99.   Lichtman, SN, and Lemasters JJ. Role of cytokines and cytokine-producing cells in reperfusion injury to the liver. Semin Liver Dis 19: 171-187, 1999[ISI][Medline].

100.   Liu, P, Fisher MA, Farhood A, Smith CW, and Jaeschke H. Beneficial effects of extracellular glutathione against endotoxin-induced liver injury during ischemia and reperfusion. Circ Shock 43: 64-70, 1994[ISI][Medline].

101.   Liu, P, McGuire GM, Fisher MA, Farhood A, Smith CW, and Jaeschke H. Activation of Kupffer cells and neutrophils for reactive oxygen formation is responsible for endotoxin-enhanced liver injury after hepatic ischemia. Shock 3: 56-62, 1995[ISI][Medline].

102.   Liu, P, Vonderfecht SL, McGuire GM, Fisher MA, Farhood A, and Jaeschke H. The 21-aminosteroid tirilazad mesylate protects in a model of endotoxin shock and acute liver failure in rats. J Pharmacol Exp Ther 271: 438-445, 1994[Abstract].

103.   Liu, P, Yin K, Nagele R, and Wong PY. Inhibition of nitric oxide synthase attenuates peroxynitrite generation, but augments neutrophil accumulation in hepatic ischemia-reperfusion in rats. J Pharmacol Exp Ther 284: 1139-1146, 1998[Abstract/Free Full Text].

104.   Lloris-Carsi, JM, Cejalvo D, Toledo-Pereyra LH, Calvo MA, and Suzuki S. Preconditioning: effect upon lesion modulation in warm liver ischemia. Transplant Proc 25: 3303-3304, 1993[ISI][Medline].

105.   Maher, JJ, Scott MK, Saito JM, and Burton MC. Adenovirus-mediated expression of cytokine-induced neutrophil chemoattractant in rat liver induces a neutrophilic hepatitis. Hepatology 25: 624-630, 1997[ISI][Medline].

106.   Manjo, G, and Joris I. Apoptosis, oncosis, and necrosis. An overview of cell death. Am J Pathol 146: 3-15, 1995[Abstract].

107.   Maroushek-Boury, N, and Czyprynski CJ. Listeria monocytogenes infection increases neutrophil adhesion and damage to a murine hepatocyte cell line in vitro. Immunol Lett 46: 111-116, 1995[ISI][Medline].

108.   Martinez-Mier, G, Toledo-Pereyra LH, McDuffie JE, Warner RL, and Ward PA. P-selectin and chemokine response after liver ischemia and reperfusion. J Am Coll Surg 191: 395-402, 2000[ISI][Medline].

109.   Mathews, WR, Guido DM, Fisher MA, and Jaeschke H. Lipid peroxidation as molecular mechanism of liver cell injury during reperfusion after ischemia. Free Radic Biol Med 16: 763-770, 1994[ISI][Medline].

110.   Mavier, P, Preaux AM, Guigui B, Lescs MC, Zafrani ES, and Dhumeaux D. In vitro toxicity of polymorphonuclear neutrophils to rat hepatocytes: evidence for a proteinase-mediated mechanism. Hepatology 8: 254-258, 1988[ISI][Medline].

111.   McCurry, KR, Campbell DA, Jr, Scales WE, Warren JS, and Remick DG. Tumor necrosis factor, interleukin 6, and the acute phase response following hepatic ischemia/reperfusion. J Surg Res 55: 49-54, 1993[ISI][Medline].

112.   McCuskey, RS. Morphological mechanisms for regulating blood flow through hepatic sinusoids. Liver 20: 3-7, 2000[ISI][Medline].

113.   McCuskey, RS, Urbaschek R, and Urbaschek B. The microcirculation during endotoxemia. Cardiovasc Res 32: 752-763, 1996[ISI][Medline].

114.   McKeown, CM, Edwards V, Phillips MJ, Harvey PR, Petrunka CN, and Strasberg SM. Sinusoidal lining cell damage: the critical injury in cold preservation of liver allografts in the rat. Transplantation 46: 178-191, 1988[ISI][Medline].

115.   Meguro, M, Katsuramaki T, Nagayama M, Kimura H, Isobe M, Kimura Y, Matsuno T, Nui A, and Hirata K. A novel inhibitor of inducible nitric oxide synthase (ONO-1714) prevents critical warm ischemia-reperfusion injury in the pig liver. Transplantation 73: 1439-1446, 2002[ISI][Medline].

116.   Menger, MD, and Vollmar B. Role of microcirculation in transplantation. Microcirculation 7: 291-306, 2000[ISI][Medline].

117.   Ming, Z, Han C, and Lautt WW. Nitric oxide mediates hepatic arterial vascular escape from norepinephrine-induced constriction. Am J Physiol Gastrointest Liver Physiol 277: G1200-G1206, 1999[Abstract/Free Full Text].

118.   Nagendra, AR, Mickelson JK, and Smith CW. CD18 integrin and CD54-dependent neutrophil adhesion to cytokine-stimulated human hepatocytes. Am J Physiol Gastrointest Liver Physiol 272: G408-G416, 1997[Abstract/Free Full Text].

119.   Nakamura, S, Nishiyama R, Serizawa A, Yokoi Y, Suzuki S, Konno H, Baba S, and Muro H. Hepatic release of endothelin-1 after warm ischemia. Transplantation 59: 679-684, 1995[ISI][Medline].

120.   Nakayama, H, Yamamoto Y, Kume M, Yamagami K, Yamamoto H, Kimoto S, Ishikawa Y, Ozaki N, Shimahara Y, and Yamaoka Y. Pharmacologic stimulation of adenosine A2 receptor supplants ischemic preconditioning in providing ischemic tolerance in rat livers. Surgery 126: 945-954, 1999[ISI][Medline].

121.   Nieminen, AL, Byrne AM, Herman B, and Lemasters JJ. Mitochondrial permeability transition in hepatocytes induced by t-BuOOH: NAD(P)H and reactive oxygen species. Am J Physiol Cell Physiol 272: C1286-C1294, 1997[Abstract/Free Full Text].

122.   Nieminen, AL, Saylor AK, Tesfai SA, Herman B, and Lemasters JJ. Contribution of the mitochondrial permeability transition to lethal injury after exposure of hepatocytes to t-butylhydroperoxide. Biochem J 307: 99-106, 1995[ISI][Medline].

123.   Nishida, J, McCuskey RS, McDonnell D, and Fox ES. Protective role of NO in hepatic microcirculatory dysfunction during endotoxemia. Am J Physiol Gastrointest Liver Physiol 267: G1135-G1141, 1994[Abstract/Free Full Text].

124.   Nishimura, Y, Takei Y, Kawano S, Goto M, Nagano K, Tsuji S, Nagai H, Ohmae A, Fusamoto H, and Kamada T. The F(ab')2 fragment of an anti-ICAM-1 monoclonal antibody attenuates liver injury after orthotopic liver transplantation. Transplantation 61: 99-104, 1996[ISI][Medline].

125.   Okuaki, Y, Miyazaki H, Zeniya M, Ishikawa T, Ohkawa Y, Tsuno S, Sakaguchi M, Hara M, Takahashi H, and Toda G. Splenectomy-reduced hepatic injury induced by ischemia/reperfusion in the rat. Liver 16: 188-194, 1996[ISI][Medline].

126.   Ozaki, M, Deshpande SS, Angkeow P, Bellan J, Lowenstein CJ, Dinauer MC, Goldschmidt-Clermont PJ, and Irani K. Inhibition of the Rac1 GTPase protects against nonlethal ischemia/reperfusion-induced necrosis and apoptosis in vivo. FASEB J 14: 418-429, 2000[Abstract/Free Full Text].

127.   Peralta, C, Bartrons R, Serafin A, Blazquez C, Guzman M, Prats N, Xaus C, Cutillas B, Gelpi E, and Rosello-Catafau J. Adenosine monophosphate-activated protein kinase mediates the protective effects of ischemic preconditioning on hepatic ischemia-reperfusion injury in the rat. Hepatology 34: 1164-1173, 2001[ISI][Medline].

128.   Peralta, C, Hotter G, Closa D, Gelpi E, Bulbena O, and Rosello-Catafau J. Protective effect of preconditioning on the injury associated to hepatic ischemia-reperfusion in the rat: role of nitric oxide and adenosine. Hepatology 25: 934-937, 1997[ISI][Medline].

129.   Peralta, C, Hotter G, Closa D, Prats N, Xaus C, Gelpi E, and Rosello-Catafau J. The protective role of adenosine in inducing nitric oxide synthesis in rat liver ischemia preconditioning is mediated by activation of adenosine A2 receptors. Hepatology 29: 126-132, 1999[ISI][Medline].

130.   Qian, T, Nieminen AL, Herman B, and Lemasters JJ. Mitochondrial permeability transition in pH-dependent reperfusion injury to rat hepatocytes. Am J Physiol Cell Physiol 273: C1783-C1792, 1997[Abstract/Free Full Text].

131.   Redaelli, CA, Tian YH, Schaffner T, Ledermann M, Baer HU, and Dufour JF. Extended preservation of rat liver graft by induction of heme oxygenase-1. Hepatology 35: 1082-1092, 2002[ISI][Medline].

132.   Rensing, H, Jaeschke H, Bauer I, Patau C, Datene V, Pannen BH, and Bauer M. Differential activation pattern of redox-sensitive transcription factors and stress-inducible dilator systems heme oxygenase-1 and inducible nitric oxide synthase in hemorrhagic and endotoxic shock. Crit Care Med 29: 1962-1971, 2001[ISI][Medline].

133.   Rentsch, M, Post S, Palma P, Lang G, Menger MD, and Messmer K. Anti-ICAM-1 blockade reduces postsinusoidal WBC adherence following cold ischemia and reperfusion, but does not improve early graft function in rat liver transplantation. J Hepatol 32: 821-828, 2000[ISI][Medline].

134.   Ricciardi, R, Foley DP, Quarfordt SH, Saavedra JE, Keefer LK, Wheeler SM, Donohue SE, Callery MP, and Meyers WC. V-PYRRO/NO: an hepato-selective nitric oxide donor improves porcine liver hemodynamics and function after ischemia reperfusion. Transplantation 71: 193-198, 2001[ISI][Medline].

135.   Rivera-Chavez, FA, Toledo-Pereyra LH, Dean RE, Crouch L, and Ward PA. Exogenous and endogenous nitric oxide but not iNOS inhibition improves function and survival of ischemically injured livers. J Invest Surg 14: 267-273, 2001[ISI][Medline].

136.   Rymsa, B, Wang JF, and de Groot H. O2-release by activated Kupffer cells upon hypoxia-reoxygenation. Am J Physiol Gastrointest Liver Physiol 261: G602-G607, 1991[Abstract/Free Full Text].

137.   Sawaya, DE, Zibari GB, Minardi A, Bilton B, Burney D, Granger DN, McDonald JC, and Brown M. P-selectin contributes to the initial recruitment of rolling and adherent leukocytes in hepatic venules after ischemia/reperfusion. Shock 12: 227-232, 1999[ISI][Medline].

138.   Schultz, RM, Marder P, Spaethe SM, Herron DK, and Sofia MJ. Effects of two leukotriene B4 (LTB4) receptor antagonists (LY255283 and SC-41930) on LTB4-induced human neutrophil adhesion and superoxide production. Prostaglandins Leukot Essent Fatty Acids 43: 267-271, 1991[ISI][Medline].

139.   Scoazec, JY, Borghi-Scoazec G, Durand F, Bernuau J, Pham BN, Belghiti J, Feldmann G, and Degott C. Complement activation after ischemia-reperfusion in human liver allografts: incidence and pathophysiological relevance. Gastroenterology 112: 908-918, 1997[ISI][Medline].

140.   Scoazec, JY, Durand F, Degott C, Delautier D, Bernuau J, Belghiti J, Benhamou JP, and Feldmann G. Expression of cytokine-dependent adhesion molecules in postreperfusion biopsy specimens of liver allografts. Gastroenterology 107: 1094-1102, 1994[ISI][Medline].

141.   Shappell, SB, Toman C, Anderson DC, Taylor AA, Entman ML, and Smith CW. Mac-1 (CD11b/CD18) mediates adherence-dependent hydrogen peroxide production by human and canine neutrophils. J Immunol 144: 2702-2711, 1990[Abstract/Free Full Text].

142.   Shen, XD, Ke B, Zhai Y, Amersi F, Gao F, Anselmo DM, Busuttil RW, and Kupiec-Weglinski JW. CD154-CD40 T-cell costimulation pathway is required in the mechanism of hepatic ischemia/reperfusion injury, and its blockade facilitates and depends on heme oxygenase-1 mediated cytoprotection. Transplantation 74: 315-319, 2002[ISI][Medline].

143.   Simonet, WS, Hughes TM, Nguyen HQ, Trebasky LD, Danilenko DM, and Medlock ES. Long-term impaired neutrophil migration in mice overexpressing human interleukin-8. J Clin Invest 94: 1310-1319, 1994[ISI][Medline].

144.   Squadrito, GL, and Pryor WA. Oxidative chemistry of nitric oxide: The role of superoxide, peroxynitrite and carbon dioxide. Free Radic Biol Med 25: 392-403, 1998[ISI][Medline].

145.   Steinhoff, G, Behrend M, Schrader B, Duijvestijn AM, and Wonigeit K. Expression pattern of leukocyte adhesion ligand molecules on human liver endothelia. Am J Pathol 142: 481-488, 1993[Abstract].

146.   Straatsburg, IH, Boermeester MA, Wolbink GJ, van Gulik TM, Gouma DJ, Frederiks WM, and Hack CE. Complement activation induced by ischemia-reperfusion in humans: a study in patients undergoing partial hepatectomy. J Hepatol 32: 783-791, 2000[ISI][Medline].

147.   Strasberg, SM. Preservation injury and donor selection: it all starts here. Liver Transpl Surg 5, Suppl 1: S1-S7, 1997.

148.   Suzuki, S, and Toledo-Pereyra LH. Interleukin 1 and tumor necrosis factor production as the initial stimulants of liver ischemia and reperfusion injury. J Surg Res 57: 253-258, 1994[ISI][Medline].

149.   Suzuki, S, Toledo-Pereyra LH, Rodriguez FJ, and Cejalvo D. Neutrophil infiltration as an important factor in liver ischemia and reperfusion injury. Modulating effects of FK506 and cyclosporine. Transplantation 55: 1265-1272, 1993[ISI][Medline].

150.   Takada, Y, Boudjema K, Jaeck D, Bel-Haouari M, Doghmi M, Chenard MP, Wolf P, and Cinqualbre J. Effects of platelet-activating factor antagonist on preservation/reperfusion injury of the graft in porcine orthotopic liver transplantation. Transplantation 59: 10-16, 1995[ISI][Medline].

151.   Teoh, N, Dela Pena A, and Farrell G. Hepatic ischemic preconditioning in mice is associated with activation of NF-kappaB, p38 kinase, and cell cycle entry. Hepatology 36: 94-102, 2002[ISI][Medline].

152.   Thiemermann, C, Ruetten H, Wu CC, and Vane JR. The multiple organ dysfunction syndrome caused by endotoxin in the rat: attenuation of liver dysfunction by inhibitors of nitric oxide synthase. Br J Pharmacol 116: 2845-2851, 1995[Abstract].

153.   Thompson, RC, and Ohlsson K. Isolation, properties, and complete amino acid sequence of human secretory leukocyte protease inhibitor, a potent inhibitor of leukocyte elastase. Proc Natl Acad Sci USA 83: 6692-6696, 1986[Abstract].

154.   Uchinami, H, Yamamoto Y, Kume M, Yonezawa K, Ishikawa Y, Taura K, Nakajima A, Hata K, and Yamaoka Y. Effect of heat shock preconditioning on NF-kappaB/I-kappaB pathway during I/R injury of the rat liver. Am J Physiol Gastrointest Liver Physiol 282: G962-G971, 2002[Abstract/Free Full Text].

155.   Vollmar, B, Glasz J, Leiderer R, Post S, and Menger MD. Hepatic microcirculatory perfusion failure is a determinant of liver dysfunction in warm ischemia-reperfusion. Am J Pathol 145: 1421-1431, 1994[Abstract].

156.   Vollmar, B, Glasz J, Menger MD, and Messmer K. Leukocytes contribute to hepatic ischemia/reperfusion injury via intercellular adhesion molecule-1-mediated venular adherence. Surgery 117: 195-200, 1995[ISI][Medline].

157.   Vollmar, B, Menger MD, Glasz J, Leiderer R, and Messmer K. Impact of leukocyte-endothelial interaction in hepatic ischemia-reperfusion injury. Am J Physiol Gastrointest Liver Physiol 267: G786-G783, 1994[Abstract/Free Full Text].

158.   Vollmar, B, Richter S, and Menger MD. Leukocyte stasis in hepatic sinusoids. Am J Physiol Gastrointest Liver Physiol 270: G798-G803, 1996[Abstract/Free Full Text].

159.   Walcher, F, Marzi I, Fischer R, Bauer M, and Larsen R. Platelet-activating factor is involved in the regulation of pathological leukocyte adhesion after liver transplantation. J Surg Res 61: 244-249, 1996[ISI][Medline].

160.   Wang, Y, Lawson JA, and Jaeschke H. Differential effect of 2-aminoethyl-isothiourea, an inhibitor of the inducible nitric oxide synthase, on microvascular blood flow and organ injury in models of hepatic ischemia-reperfusion injury and endotoxemia. Shock 10: 20-25, 1998[ISI][Medline].

161.   Wang, Y, Mathews WR, Guido DM, Farhood A, and Jaeschke H. Inhibition of nitric oxide synthesis aggravates reperfusion injury after hepatic ischemia and endotoxemia. Shock 4: 282-288, 1995[ISI][Medline].

162.   Wang, Y, Vodovotz Y, Kim PK, Zamora R, and Billiar TR. Mechanisms of hepatoprotection by nitric oxide. Ann NY Acad Sci 962: 415-422, 2002[Abstract/Free Full Text].

163.   Weiss, SJ. Tissue destruction by neutrophils. N Engl J Med 320: 365-376, 1989[ISI][Medline].

164.   Wheeler, MD, Katuna M, Smutney OM, Froh M, Dikalova A, Mason RP, Samulski RJ, and Thurman RG. Comparison of the effect of adenoviral delivery of three superoxide dismutase genes against hepatic ischemia-reperfusion injury. Hum Gene Ther 12: 2167-2177, 2001[ISI][Medline].

165.   Wiest, R, and Groszmann RJ. The paradox of nitric oxide in cirrhosis and portal hypertension: too much, not enough. Hepatology 35: 478-491, 2002[ISI][Medline].

166.   Witthaut, R, Farhood A, Smith CW, and Jaeschke H. Complement and tumor necrosis factor-alpha contribute to Mac-1 (CD11b/CD18) upregulation and systemic neutrophil activation during endotoxemia in vivo. J Leukoc Biol 55: 105-111, 1994[Abstract].

167.   Wong, J, Johnston B, Lee SS, Bullard DC, Smith CW, Beaudet AL, and Kubes P. A minimal role for selectins in the recruitment of leukocytes into the inflamed liver microvasculature. J Clin Invest 99: 2782-2790, 1997[Abstract/Free Full Text].

168.   Yabe, Y, Kobayashi N, Nishihashi T, Takahashi R, Nishikawa M, Takakura Y, and Hashida M. Prevention of neutrophil-mediated hepatic ischemia/reperfusion injury by superoxide dismutase and catalase derivatives. J Pharmacol Exp Ther 298: 894-899, 2001[Abstract/Free Full Text].

169.   Yadav, SS, Howell DN, Steeber DA, Harland RC, Tedder TF, and Clavien PA. P-selectin mediates reperfusion injury through neutrophil and platelet sequestration in the warm ischemic mouse liver. Hepatology 29: 1494-1502, 1999[ISI][Medline].

170.   Yin, DP, Sankary HN, Chong AS, Ma LL, Shen J, Foster P, and Williams JW. Protective effect of ischemic preconditioning on liver preservation-reperfusion injury in rats. Transplantation 66: 152-157, 1998[ISI][Medline].

171.   Yokoyama, Y, Baveja R, Sonin N, Nakanishi K, Zhang JX, and Clemens MG. Altered endothelin receptor subtype expression in hepatic injury after ischemia/reperfusion. Shock 13: 72-78, 2000[ISI][Medline].

172.   Yonezawa, K, Yamamoto Y, Yamamoto H, Ishikawa Y, Uchinami H, Taura K, Nakajima A, and Yamaoka Y. Suppression of tumor necrosis factor-alpha production and neutrophil infiltration during ischemia-reperfusion injury of the liver after heat shock preconditioning. J Hepatol 35: 619-627, 2001[ISI][Medline].

173.   Yoshidome, H, Kato A, Edwards MJ, and Lentsch AB. Interleukin-10 suppresses hepatic ischemia/reperfusion injury in mice: implications of a central role for nuclear factor kappaB. Hepatology 30: 203-208, 1999[ISI][Medline].

174.   Yoshidome, H, Kato A, Miyazaki M, Edwards MJ, and Lentsch AB. IL-13 activates STAT6 and inhibits liver injury induced by ischemia/reperfusion. Am J Pathol 155: 1059-1064, 1999[Abstract/Free Full Text].

175.   Zhang, B, Borderie D, Sogni P, Soubrane O, Houssin D, and Calmus Y. NO-mediated vasodilation in the rat liver. Role of hepatocytes and liver endothelial cells. J Hepatol 26: 1348-1355, 1997[ISI][Medline].

176.   Zhang, P, Xie M, Zagorski J, and Spitzer JA. Attenuation of hepatic neutrophil sequestration by anti-CINC antibody in endotoxic rats. Shock 4: 262-268, 1995[ISI][Medline].

177.   Zhou, W, McCollum MO, Levine BA, and Olson MS. Inflammation and platelet-activating factor production during hepatic ischemia/reperfusion. Hepatology 16: 1236-1240, 1992[ISI][Medline].

178.   Zhou, W, Zhang Y, Hosch MS, Lang A, Zwacka RM, and Engelhardt JF. Subcellular site of superoxide dismutase expression differentially controls AP-1 activity and injury in mouse liver following ischemia/reperfusion. Hepatology 33: 902-914, 2001[ISI][Medline].

179.   Zou, XM, Yagihashi A, Hirata K, Tsuruma T, Matsuno T, Tarumi K, Asanuma K, and Watanabe N. Downregulation of cytokine-induced neutrophil chemoattractant and prolongation of rat liver allograft survival by interleukin-10. Surg Today 28: 184-191, 1998[Medline].

180.   Zwacka, RM, Zhang Y, Halldorson J, Schlossberg H, Dudus L, and Engelhardt JF. CD4(+) T-lymphocytes mediate ischemia/reperfusion-induced inflammatory responses in mouse liver. J Clin Invest 100: 279-289, 1997[Abstract/Free Full Text].

181.   Zwacka, RM, Zhou W, Zhang Y, Darby CJ, Dudus L, Halldorson J, Oberley L, and Engelhardt JF. Redox gene therapy for ischemia/reperfusion injury of the liver reduces AP1 and NF-kappaB activation. Nat Med 4: 698-704, 1998[ISI][Medline].


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