Ischaemia/reperfusion injury is an important cause of liver damage during surgical procedures such as hepatic resection and liver transplantation, and represents the main cause of graft dysfunction post-transplantation. Molecular processes occurring during hepatic ischaemia/reperfusion are diverse, and continuously include new and complex mechanisms. The present review aims to summarize the newest concepts and hypotheses regarding the pathophysiology of liver ischaemia/reperfusion, making clear distinction between situations of cold and warm ischaemia. Moreover, the most updated therapeutic strategies including pharmacological, genetic and surgical interventions, as well as some of the scientific controversies in the field are described.

INTRODUCTION

The pathophysiology of I/R (ischaemia/reperfusion) injury has been comprehensively studied, and reviewed, by several authors in the past [1,2]. One might suggest that similar underlying events happen in all types of clinical situations where I/R occurs, and that the mediators and mechanisms involved are solidly established. Nevertheless, the more we discover, the less we certainly know about I/R injury, and thus the further away seems to be its solution at the bedside.

The complexity in mechanisms and cellular components implicated in I/R has led to several controversies, and even discrepancies, in our understanding of this pathology. Carefully reading the literature, we hypothesize that disagreements in I/R mechanisms, and therefore in therapeutic targets, were probably due to slight (or evident) differences in experimental procedures. The present mini-review aims to summarize some of the most recently described cellular and molecular mechanisms underlying hepatic I/R injury, as well as derived therapeutic options, making a patent distinction between those results obtained in experimental models of cold and warm ischaemia. In addition, some of the most controversial (and long-lasting) observations in the field are also discussed.

COLD STORAGE

Mechanisms of injury

Hepatocyte and sinusoidal injuries

Nowadays, it is accepted that hepatic endothelium damage occurring during cold preservation represents the initial factor leading to hepatic I/R injury, determining poor graft microcirculation, platelet activation, persistent vasoconstriction, up-regulation of adhesion molecules, cytokine release, oxidative stress, Kupffer cell activation, neutrophil infiltration and hepatocyte death, thus contributing to the development of primary non-function or impaired primary function after liver transplantation (Figure 1). Indeed, and although hepatocyte function and viability might be preserved under in vitro cold storage conditions up to 72 h, the LSEC (liver sinusoidal endothelial cells) phenotype is rapidly deregulated during cold storage, becoming activated after 6 h, and highly apoptotic and pro-inflammatory thereafter [3,4]. In fact, experimental studies of liver preservation for transplantation showed acute endothelial dysfunction development after 16 h of cold storage, associated with significant hepatocellular injury and death [4]. Considering the intimate cellular cross-talk between LSEC and hepatocytes, it is very possible that LSEC injury due to cold storage may negatively affect hepatocyte viability, and vice versa.

Underlying mechanisms of hepatic cold ischaemia and warm reperfusion injury
Figure 1
Underlying mechanisms of hepatic cold ischaemia and warm reperfusion injury

Pathways recently described are coloured, whereas classic mechanisms are summarized in grey. DAMPs, damage-associated molecular patterns; eNOS, endothelial nitric oxide synthase; ET, endothelin; IL, interleukin; IRF-1, interferon regulatory factor-1; KC, Kupffer cells; KLF2, Krüppel-like factor 2; LSEC, liver sinusoidal endothelial cells; Nrf2, nuclear factor-erythroid 2-related factor 2; PAMPs, pathogen-associated molecular patterns; ROS, reactive oxygen species; TLR4, Toll-like receptor 4; TM, thrombomodulin; TNF-α, tumour necrosis factor α.

Figure 1
Underlying mechanisms of hepatic cold ischaemia and warm reperfusion injury

Pathways recently described are coloured, whereas classic mechanisms are summarized in grey. DAMPs, damage-associated molecular patterns; eNOS, endothelial nitric oxide synthase; ET, endothelin; IL, interleukin; IRF-1, interferon regulatory factor-1; KC, Kupffer cells; KLF2, Krüppel-like factor 2; LSEC, liver sinusoidal endothelial cells; Nrf2, nuclear factor-erythroid 2-related factor 2; PAMPs, pathogen-associated molecular patterns; ROS, reactive oxygen species; TLR4, Toll-like receptor 4; TM, thrombomodulin; TNF-α, tumour necrosis factor α.

Liver sinusoidal cells

It is well known that LSEC of cold-stored livers are seriously compromised during cold storage and transplantation. Indeed, rapid repopulation of LSEC is observed after transplantation in association with up-regulation of diverse pro-angiogenic and endothelial-survival mechanisms. In this setting, potential recruitment and engraftment of bone-marrow-derived endothelial precursors may contribute to revascularization sites [5]. In the last few years, several studies have revealed new signalling mechanisms involved in cold ischaemia injury where sinusoidal cells play a key role. The lack of biomechanical stimuli occurring during cold preservation for transplantation markedly deteriorates the LSEC protective phenotype by down-regulating the expression of the transcription factor KLF2 (Krüppel-like factor 2), which orchestrates the transcription of a variety of protective genes including the eNOS (endothelial nitric oxide synthase), the anti-thrombotic molecule thrombomodulin or the antioxidant transcription factor Nrf2 (nuclear factor-erythroid 2-related factor 2) [4,6].

Concomitantly to LSEC deregulation, Kupffer cells suffer from a profound activation process that is promoted by the release of DAMPs (damage-associated molecular patterns) from neighbouring necrotic hepatic cells and, under conditions of sepsis or endotoxaemia, also PAMPs (pathogen-associated molecular patterns). TLRs (Toll-like receptors) recognize both PAMPs and DAMPs, leading to activation of downstream signalling cascades. Evidence from experimental studies of cold ischaemia and transplantation indicates that an increase in TLR4 could be correlated with hepatocellular damage [7]. Although this occurs in non-steatotic livers, up-regulation of the TLR4 pathway is protective in steatotic livers undergoing transplantation [8]. This divergent role for TLR4 could be explained by differences in the pathogenic mechanisms of I/R injury between steatotic and non-steatotic livers.

Emerging mechanisms of injury

The autophagy machinery is activated under stress conditions, such as transient hypoxia or starvation, to ensure cell survival and limit cell death. Under experimental conditions of cold I/R injury, it has been found that defective liver autophagy correlates with liver damage [9]. In fact, strategies aimed at up-regulating autophagy reduced the development of hepatocellular necrosis and improved graft survival; nevertheless, better characterization of this process, focusing on each hepatic cell type, is still necessary. In this regard, a recent communication by Biel and colleagues presented at the AASLD Liver Meeting 2014 (abstract 105) demonstrated that hepatocyte autophagy defect during I/R leads to cell death, therefore proposing activation of hepatocyte autophagy as a new therapeutic option.

Small non-coding RNAs, and particularly miRNAs, have emerged as important genetic regulators of cellular processes, including tissue injury and repair responses. Recently, it has been demonstrated that the levels of the HDmiRs (hepatocyte-derived miRNAs) miR-122, miR-148a and miR-194 are significantly elevated in serum from patients after liver transplantation, positively correlating with aminotransferase levels [10]. As experimental studies have shown that miRNAs are feasible targets for therapeutic interventions designed to minimize injury caused by ischaemic insults, further studies targeting HDmiRs might elucidate their real role in cold I/R injury.

IRF (interferon-regulatory factor)-1, a transcription factor originally identified as a regulator of IFN (interferon) α/β, is involved in many aspects of innate and adaptive immune responses. It has been described that IRF-1-mediated inflammation after liver transplantation is involved in multiple mechanisms that are vital to the cellular stress response, including production of inflammatory mediators, activation of apoptotic pathways and activation of MAPK (mitogen-activated protein kinase) pathways [11]. Importantly, antagonism or silencing of IRF-1 gene expression may be a potential strategy to ameliorate liver damage associated with cold preservation injury [12].

B7-H1 (B7 homologue 1) is a recently identified member of the B7 family with important regulatory functions in cell-mediated immune responses. In experimental models of liver transplantation, B7-H1 is up-regulated in both parenchymal and non-parenchymal cells ameliorating cold I/R injury. Indeed, B7-H1 inhibition markedly worsens I/R injury through increased infiltration and reduced apoptosis of CD8+ T-cells in liver grafts [13].

Finally, it is worth considering recent findings indicating that brain death itself strongly reduces the tolerance of liver grafts to cold I/R injury [14,15]. Indeed, donor brain death triggers a systemic inflammatory response and increased immunogenicity of the graft that could potentially lead to reduced organ function. Injurious effects of brain death are mainly mediated through Kupffer cell activation, leading to TNFα (tumour necrosis factor α) and TLR4 amplification. Considering that 80% of organs used in the clinic come from donors who suffered brain death [14], it seems reasonable to include brain death as part of the protocol in experimental studies investigating cold I/R injury. This patent difference in the protocol might positively influence the ratio of therapeutic strategies that are successfully translated to the bedside.

Controversies

Role of warm ischaemia (after cold) in hepatic injury

The injury process that begins during hypothermia is afterwards fostered by the re-warming process during graft implantation. Concretely, in the liver, when temperature and cell metabolism ramps up, damage switches from the more cold-sensitive LSEC to the warm ischaemia-sensitive hepatocytes [16]. In the light of these findings, one might assume that normothermic preservation [using NMP (normothermic machine perfusion)] would probably be the most appropriate strategy to preserve grafts in the clinical setting of liver transplantation. Indeed, it would avoid the transition of cold to warm ischaemia, maintaining the liver graft at a single temperature from retrieval until implantation. The underlying principle of NMP is the combination of continuous circulation of metabolic substrates for ATP regeneration and removal of waste products, together with biomechanical stimulation of the sinusoids. Accordingly, accumulating evidence demonstrates the superiority of the more physiological approach of normothermia, in association with an oxygenated blood-based perfusion solution, in comparison with cold storage procedures [1719]. Furthermore, in situ normothermic regional perfusion of donation after cardiac death is gaining in popularity and has resulted in a number of successful liver transplantations [2024].

Therapeutic approaches

On the basis of the above-described mechanisms, a variety of therapeutic strategies have been developed. As seen in Table 1, in the last 2 years the development of strategies to protect marginal liver grafts has predominated, thus indicating the concern about the increase in waiting list times and the shortage of liver grafts available for transplantation; also, considerable efforts have been devoted to the improvement in perfusion machine techniques, and the first strategies based on cell therapy against cold I/R injury have been reported. Interestingly, most of these original investigations devoted their efforts to molecular pathways and pathophysiological events markedly different from those studied in previous decades (i.e. note the switch from strategies broadly targeting adhesion molecules to strategies specifically focused on upstream events of inflammation, such as adipocytokine signalling). In addition, in the specific scenario of machine perfusion, a significant part of work aimed to characterize the possible use of oxygenated perfusion solutions, thus challenging the dogma of noxious effects of oxygen during reperfusion injury. In fact, very recently, a new preservation modality has been described that combines machine perfusion at subnormothermic conditions with a new haemoglobin-based oxygen carrier solution, triggering regenerative and cell protective responses resulting in improved allograft function [25].

Table 1
Therapeutic approaches against cold I/R injury

AMPK, AMP-activated protein kinase; Bcl-2, B-cell lymphoma 2; DCD, donations after cardiac death; eNOS, endothelial nitric oxide synthase; ER, endoplasmic reticulum; ERK, extracellular-signal-regulated kinase; ET-1, endothelin 1; GABAR, γ-aminobutyric acid receptor; HO-1, haem oxygenase-1; IFN, interferon; IL, interleukin; iNOS, inducible nitric oxide synthase; LDH, lactate dehydrogenase; LSEC, liver sinusoidal endothelial cells; MMP, matrix metalloproteinase; MSC-CM, mesenchymal stem cell-conditioned medium; NHBD, non-heart-beating donors; NF-κB, nuclear factor κB; NKT, natural killer T-cell; NMP, normothermic machine perfusion; Nrf2, nuclear factor-erythroid 2-related factor 2; PI3K, phosphoinositide 3-kinase; PGE1, prostaglandin E1; PPAR, peroxisome-proliferator-activated receptor; rMnSOD, recombinant MnSOD; SLC, sinusoidal lining cell; SOD, superoxide dismutase; SOWP, short oxygenated warm perfusion; STAT, signal transducer and activator of transcription; TIM-1, T-cell immunoglobulin mucin 1; TLR, Toll-like receptor; TNF, tumour necrosis factor; UW, University of Wisconsin; VEGF, vascular endothelial growth factor.

(a) Pharmacological strategies
DrugSpeciesExperimental modelCold ischaemia timeEffect
Adiponectin [40] (adipocytokine) Rat Liver transplantation (steatotic grafts) 6 h ↓ Hepatic injury; ↑ PI3K/Akt 
ανβ6 Antibody [41] (ανβ6 integrin) Mouse Liver transplantation 12 h ↓ Progression of biliary fibrosis; ↑ liver function 
Biliverdin [42] (green tetrapyrrolic bile pigment) Pig Ex vivo liver perfusion 19 h ↓ Hepatic injury, neutrophil infiltration and apoptosis; ↑ liver function 
Bortezomib [43] (26S proteasome) Rat Liver transplantation (steatotic grafts) 2 h ↓ Hepatic injury, NF-κB, MMP and pro-inflammatory cytokines 
Cardiotrophin-1 [44] (cytokine) Pig Liver transplantation 4 h ↓ Hepatic injury, caspase 3, IL-1β, IL-6, TNFα, oxidative stress; ↑ survival, Akt, ERK, STAT3 
Edaravone [45] (neuroprotective agent) Pig Liver transplantation (NHBD liver grafts) 4 h ↓ Hepatic injury and SLC damage; ↑ survival 
Fructose [46] (monosaccharide) Rat Ex vivo liver perfusion 26 h ↓ Hepatic injury; ↑ ATP 
GABAR agonist [47] (γ-aminobutyric acid) Rat Split liver transplantation 2 h ↓ Hepatic injury, oxidative stress and apoptosis 
Ketanserin [48] (serotonin 2A receptor antagonist) Rat Liver transplantation (DCD liver grafts) 4 h ↓ Hepatic injury, biliary fibrosis, liver serotonin and hidroxyproline; ↑ biliary function 
Magnesium [49Human Living donor liver transplantation Not reported ↓ Hepatic injury; regulation of Th1-to-Th2 cytokine balance towards Th2 
5′-Methylthioadenosine [50] (nucleoside) Rat Liver transplantation Not reported ↓ Hepatic injury, NF-κB and MAPK activation 
N-acetylcysteine [51] (antioxidant) Human Liver transplantation 2–10 h ↓ Post-operative complications; ↑ survival 
Perfluorodecalin [52] (perfluorocarbon) Rat Hypothermic perfusion (DCD liver grafts) 8 h ↓ Hepatic injury; ↑ survival 
Resistin [40] (adipocytokine) Rat Liver transplantation (steatotic grafts) 6 h ↓ Hepatic injury; ↑ PI3K/Akt 
rMnSOD [37] (antioxidant) Rat Ex vivo liver perfusion 16 h ↓ Hepatic injury and inflammation; ↑ hepatic microcirculation and endothelial function 
RMT1-10 [53] (TIM-1 blocker) Mice Liver transplantation 20 h ↓ Hepatic injury and neutrophil and macrophage activation; ↑ IL-4, IL-10, IL-22, Bcl-2 
Simvastatin [54] (vasoprotector) Rat Ex vivo liver perfusion (steatotic grafts) 16 h ↓ Hepatic injury, apoptosis and inflammation; ↑ hepatic microcirculation and endothelial function 
(b) Gene and cell therapy strategies
Target gene/cell therapy strategySpeciesExperimental modelCold ischaemia timeEffect
Ad-hTERT [55] (human telomerase transcriptase) Rat Liver transplantation (aged grafts) 2 h ↓ Hepatic injury and apoptosis; ↑ telomerase activity 
CD39−/− in myeloid dendritic cells [56Mouse Liver transplantation 24 h ↓ Hepatic injury; ↑ pro-inflammatory cytokines 
CD39-transgenic [57] (CD39-overexpression) Mouse Liver transplantation 18 h ↓ Hepatic injury, IL-6, CD4+ T-cells and invariant NKT cells 
Keap1-deficient [58] (Keap1 hepatocyte-specific knockout) Mouse Liver transplantation 20 h ↓ Hepatic injury, oxidative stress and inflammation and apoptosis; ↑ Nrf2, thioredoxin and PI3K/Akt 
MSC-CM [59] (mesenchymal stem cells) Rat Reduced-size liver transplantation 55–65 min ↓ Activation of Kupffer cells and neutrophils, pro-inflammatory cytokines and apoptosis; ↑ VEGF, MMP-9 and proliferating hepatocytes and LSEC 
(c) Additives for preservation solutions
Drug or additiveSpeciesExperimental modelCold ischaemia timeEffect
Bortezomib in UW or IGL solution [60,61] (proteasome inhibitor) Rat Ex vivo liver perfusion (steatotic grafts) 24 h ↓ Hepatic injury, oxidative stress, IL-1 and TNF-α; ↑ NO and AMPK 
Desferrioxamine in UW solution [62] (bacterial siderophore) Rat Ex vivo liver perfusion 20 h ↓ Hepatic injury 
Melatonin and trimetazidine in IGL-1 solution [63] (hormone and anti-ischaemic drug) Rat Ex vivo liver perfusion (steatotic grafts) 24 h ↓ Hepatic injury and ER stress; ↑ autophagy 
rMnSOD in Celsior solution [37] (antioxidant) Human Ex vivo preservation 16 h ↓ Oxidative stress 
SNO-HSA in UW solution [64] (S-nitrosated human serum albumin) Rat Ex vivo liver perfusion 72 h ↓ Hepatic injury, LDH, oxidative stress and apoptosis 
SOWP and PGE1 in UW solution [65] (short oxygenated warm perfusion and prostaglandin E1Rat Ex vivo liver perfusion (uncontrolled NHBD grafts) 6 h ↓ Hepatic injury, necrosis and apoptosis 
(d) Surgical and machine perfusion-based strategies
StrategySpeciesExperimental model/clinical settingCold ischaemia timeEffect
HOPE [66,67] (hypothermic oxygenated perfusion) Rat Liver transplantation (DCD liver grafts) 4 h ↓ Hepatic injury, biliary injury, Kupffer and endothelial cell activation and oxidative stress; ↑ survival 
HOPE [68] (hypothermic oxygenated perfusion) Pig Ex vivo liver perfusion model (DCD liver grafts) 6 h ↓ Hepatic injury and endothelial and mitochondrial damage 
IPC [69] (ischaemic pre-conditioning) Rat Liver transplantation 50 min ↓ Hepatic injury and bacterial translocation; ↑ intestinal microbiota and mucosal ultrastructure 
NMP [70] (normothermic machine perfusion) Rat Liver transplantation (DCD liver grafts) No cold ischaemia Organ stability over 5–6 h of perfusion; restoration of warm ischaemic liver to a likely transplantable state after 2 h of perfusion 
Machine perfusion [71Pig Liver transplantation (DCD liver grafts) 2 h ↓ Hepatic injury; ↑ recovery and resuscitation of DCD liver grafts 
RIPostC [72] (remote ischaemic post-conditioning) Human Living donor liver transplantation 76-83 min ↓ Acute kidney injury; no improvements in postoperative liver graft function or clinical outcomes 
Subnormothermic machine perfusion combined with haemoglobin-based oxygen carrier (HBOC) solution [25Pig Liver transplantation 9 h ↓ Hepatic injury, IFNα, IFNγ, TNFα, IL-1β, IL-4; ↑ liver function, survival 
VSOP-NO [73,74] (venous systemic oxygen persufflation using NO gas) Rat Liver transplantation (small or steatotic grafts) 3 h ↓ Hepatic injury, iNOS and peroxinitrite; ↑ regeneration, eNOS expression, viability and microcirculation 
VSOP-NO [75] (venous systemic oxygen persufflation using NO gas) Rat Liver transplantation (DCD liver grafts) 3 h ↓ Hepatic injury, oxidative stress, TNFα, IL-6, eNOS, ET-1, hepatocyte and LSEC damage 
(a) Pharmacological strategies
DrugSpeciesExperimental modelCold ischaemia timeEffect
Adiponectin [40] (adipocytokine) Rat Liver transplantation (steatotic grafts) 6 h ↓ Hepatic injury; ↑ PI3K/Akt 
ανβ6 Antibody [41] (ανβ6 integrin) Mouse Liver transplantation 12 h ↓ Progression of biliary fibrosis; ↑ liver function 
Biliverdin [42] (green tetrapyrrolic bile pigment) Pig Ex vivo liver perfusion 19 h ↓ Hepatic injury, neutrophil infiltration and apoptosis; ↑ liver function 
Bortezomib [43] (26S proteasome) Rat Liver transplantation (steatotic grafts) 2 h ↓ Hepatic injury, NF-κB, MMP and pro-inflammatory cytokines 
Cardiotrophin-1 [44] (cytokine) Pig Liver transplantation 4 h ↓ Hepatic injury, caspase 3, IL-1β, IL-6, TNFα, oxidative stress; ↑ survival, Akt, ERK, STAT3 
Edaravone [45] (neuroprotective agent) Pig Liver transplantation (NHBD liver grafts) 4 h ↓ Hepatic injury and SLC damage; ↑ survival 
Fructose [46] (monosaccharide) Rat Ex vivo liver perfusion 26 h ↓ Hepatic injury; ↑ ATP 
GABAR agonist [47] (γ-aminobutyric acid) Rat Split liver transplantation 2 h ↓ Hepatic injury, oxidative stress and apoptosis 
Ketanserin [48] (serotonin 2A receptor antagonist) Rat Liver transplantation (DCD liver grafts) 4 h ↓ Hepatic injury, biliary fibrosis, liver serotonin and hidroxyproline; ↑ biliary function 
Magnesium [49Human Living donor liver transplantation Not reported ↓ Hepatic injury; regulation of Th1-to-Th2 cytokine balance towards Th2 
5′-Methylthioadenosine [50] (nucleoside) Rat Liver transplantation Not reported ↓ Hepatic injury, NF-κB and MAPK activation 
N-acetylcysteine [51] (antioxidant) Human Liver transplantation 2–10 h ↓ Post-operative complications; ↑ survival 
Perfluorodecalin [52] (perfluorocarbon) Rat Hypothermic perfusion (DCD liver grafts) 8 h ↓ Hepatic injury; ↑ survival 
Resistin [40] (adipocytokine) Rat Liver transplantation (steatotic grafts) 6 h ↓ Hepatic injury; ↑ PI3K/Akt 
rMnSOD [37] (antioxidant) Rat Ex vivo liver perfusion 16 h ↓ Hepatic injury and inflammation; ↑ hepatic microcirculation and endothelial function 
RMT1-10 [53] (TIM-1 blocker) Mice Liver transplantation 20 h ↓ Hepatic injury and neutrophil and macrophage activation; ↑ IL-4, IL-10, IL-22, Bcl-2 
Simvastatin [54] (vasoprotector) Rat Ex vivo liver perfusion (steatotic grafts) 16 h ↓ Hepatic injury, apoptosis and inflammation; ↑ hepatic microcirculation and endothelial function 
(b) Gene and cell therapy strategies
Target gene/cell therapy strategySpeciesExperimental modelCold ischaemia timeEffect
Ad-hTERT [55] (human telomerase transcriptase) Rat Liver transplantation (aged grafts) 2 h ↓ Hepatic injury and apoptosis; ↑ telomerase activity 
CD39−/− in myeloid dendritic cells [56Mouse Liver transplantation 24 h ↓ Hepatic injury; ↑ pro-inflammatory cytokines 
CD39-transgenic [57] (CD39-overexpression) Mouse Liver transplantation 18 h ↓ Hepatic injury, IL-6, CD4+ T-cells and invariant NKT cells 
Keap1-deficient [58] (Keap1 hepatocyte-specific knockout) Mouse Liver transplantation 20 h ↓ Hepatic injury, oxidative stress and inflammation and apoptosis; ↑ Nrf2, thioredoxin and PI3K/Akt 
MSC-CM [59] (mesenchymal stem cells) Rat Reduced-size liver transplantation 55–65 min ↓ Activation of Kupffer cells and neutrophils, pro-inflammatory cytokines and apoptosis; ↑ VEGF, MMP-9 and proliferating hepatocytes and LSEC 
(c) Additives for preservation solutions
Drug or additiveSpeciesExperimental modelCold ischaemia timeEffect
Bortezomib in UW or IGL solution [60,61] (proteasome inhibitor) Rat Ex vivo liver perfusion (steatotic grafts) 24 h ↓ Hepatic injury, oxidative stress, IL-1 and TNF-α; ↑ NO and AMPK 
Desferrioxamine in UW solution [62] (bacterial siderophore) Rat Ex vivo liver perfusion 20 h ↓ Hepatic injury 
Melatonin and trimetazidine in IGL-1 solution [63] (hormone and anti-ischaemic drug) Rat Ex vivo liver perfusion (steatotic grafts) 24 h ↓ Hepatic injury and ER stress; ↑ autophagy 
rMnSOD in Celsior solution [37] (antioxidant) Human Ex vivo preservation 16 h ↓ Oxidative stress 
SNO-HSA in UW solution [64] (S-nitrosated human serum albumin) Rat Ex vivo liver perfusion 72 h ↓ Hepatic injury, LDH, oxidative stress and apoptosis 
SOWP and PGE1 in UW solution [65] (short oxygenated warm perfusion and prostaglandin E1Rat Ex vivo liver perfusion (uncontrolled NHBD grafts) 6 h ↓ Hepatic injury, necrosis and apoptosis 
(d) Surgical and machine perfusion-based strategies
StrategySpeciesExperimental model/clinical settingCold ischaemia timeEffect
HOPE [66,67] (hypothermic oxygenated perfusion) Rat Liver transplantation (DCD liver grafts) 4 h ↓ Hepatic injury, biliary injury, Kupffer and endothelial cell activation and oxidative stress; ↑ survival 
HOPE [68] (hypothermic oxygenated perfusion) Pig Ex vivo liver perfusion model (DCD liver grafts) 6 h ↓ Hepatic injury and endothelial and mitochondrial damage 
IPC [69] (ischaemic pre-conditioning) Rat Liver transplantation 50 min ↓ Hepatic injury and bacterial translocation; ↑ intestinal microbiota and mucosal ultrastructure 
NMP [70] (normothermic machine perfusion) Rat Liver transplantation (DCD liver grafts) No cold ischaemia Organ stability over 5–6 h of perfusion; restoration of warm ischaemic liver to a likely transplantable state after 2 h of perfusion 
Machine perfusion [71Pig Liver transplantation (DCD liver grafts) 2 h ↓ Hepatic injury; ↑ recovery and resuscitation of DCD liver grafts 
RIPostC [72] (remote ischaemic post-conditioning) Human Living donor liver transplantation 76-83 min ↓ Acute kidney injury; no improvements in postoperative liver graft function or clinical outcomes 
Subnormothermic machine perfusion combined with haemoglobin-based oxygen carrier (HBOC) solution [25Pig Liver transplantation 9 h ↓ Hepatic injury, IFNα, IFNγ, TNFα, IL-1β, IL-4; ↑ liver function, survival 
VSOP-NO [73,74] (venous systemic oxygen persufflation using NO gas) Rat Liver transplantation (small or steatotic grafts) 3 h ↓ Hepatic injury, iNOS and peroxinitrite; ↑ regeneration, eNOS expression, viability and microcirculation 
VSOP-NO [75] (venous systemic oxygen persufflation using NO gas) Rat Liver transplantation (DCD liver grafts) 3 h ↓ Hepatic injury, oxidative stress, TNFα, IL-6, eNOS, ET-1, hepatocyte and LSEC damage 

WARM ISCHAEMIA

Mechanisms of injury

Warm I/R injury is responsible for significant organ dysfunction and failure after liver resection and haemorrhagic shock. Historically, it has been considered that hepatocytes are more sensitive to warm I/R, whereas LSEC are more sensitive to cold I/R. However, limitation of injury to a particular cell type is rare under pathophysiological conditions; indeed evidence suggest profound sinusoidal deregulation during warm I/R injury [26]. Similarly to liver cold I/R injury, Kupffer cells play a key role in warm I/R injury being a source of many pro-inflammatory mediators. Neutrophils are also activated and recruited into the liver, where several factors and conditions determine that neutrophils migrate out of the sinusoids and affect parenchymal cells [26].

A central underlying mechanism for parenchymal injury due to warm I/R injury is the impairment of mitochondria. Interestingly, recent data indicate that cardiolipin (diphosphatidylglycerol), a phospholipid required for efficient mitochondrial function, may play an essential role in such injury. Indeed, warm I/R causes a significant decrease in hepatic cardiolipin content that, together with an increase in its oxidized form, impairs mitochondrial function, altogether worsening liver injury [27]. Strategies that support cardiolipin synthesis, or prevent its oxidation, may be beneficial to reduce I/R injury in the liver.

Emerging evidence reveals the role of acetylation in fundamental biological processes. Protein acetylation by histone acetyltransferases enhances gene expression via relaxation of chromatin and transcription activation. Acetylation homoeostasis is often disrupted in several pathologies. Indeed, warm hepatic I/R injury is accompanied by a significant reduction in histone acetylation in the liver, suggesting that histone acetylation may play an important role in I/R injury representing a new therapeutic strategy to ameliorate this pathology [28].

MMP (matrix metalloproteinase)-9, an inducible gelatinase, is emerging as a central mediator of leucocyte trafficking into inflamed tissues. In a mouse model of steatotic liver undergoing warm I/R injury, it was demonstrated that MMP-9 activity disrupts vascular integrity through a PECAM-1 (platelet endothelial cell adhesion molecule-1)-dependent mechanism, and interferes with liver regeneration [29]. Similar findings were observed characterizing MMP-10 [30], thus suggesting that MMP-9/10-targeted therapies would allow more patients to undergo successful liver resection, especially those with fatty liver, who exhibit higher susceptibility to I/R.

Adipose tissue and adipocytokines

It has been suggested that, in conditions of PH (partial hepatectomy) without I/R, adipose tissue supplies the energy needed by the remnant liver. Considering that, in clinical practice, PH is usually accompanied by I/R, a recent study has evaluated the contribution of adipose tissue to liver injury and regeneration observed in these surgical conditions. This study demonstrated that adipose tissue is not required for the regeneration of non-steatotic livers; however, it is necessary to promote regeneration and diminish injury in steatotic ones. Interestingly, adipose tissue does not seem to be an energy source for the steatotic liver; indeed ATP levels were maintained after lipectomy, but adipose tissue is a source of different adipocytokines, which are essential signals for liver regeneration [31].

Several adipocytokines may play a role in warm I/R injury; however, very little is known about them. In the setting of I/R injury without PH, adiponectin protects non-steatotic livers by an AMPK (AMP-activated protein kinase)/eNOS mechanism [32]. Contrarily, this hormone is accumulated in steatotic livers upon warm I/R injury through a MAPK-mediated mechanism, promoting exacerbation of oxidative stress and liver injury [33]. Therefore the response of livers to adiponectin may very much depend on their basal phenotype, involving different transduction pathways.

RBP4 (retinol-binding protein 4), resistin and visfatin have been characterized in experimental models of PH under warm I/R. In this sense, RBP4 exerts injurious effects in steatotic and non-steatotic livers, and its modulation further worsens the liver outcome, thus it is not advised as a therapeutic strategy [34]. More recently, a relationship between resistin and visfatin has been described [35]. Although no evident role for these adipocytokines was observed in non-steatotic livers, in steatotic livers endogenous resistin maintained low levels of visfatin by blocking its hepatic uptake from the circulation, thus regulating the visfatin detrimental effects on hepatic damage and regenerative failure. NAD biosynthetic activity, rather than inflammatory response-like activity, was responsible for the injurious effects of visfatin in steatotic livers. This study indicates the clinical potential of visfatin-blocking-based therapies in steatotic livers submitted to I/R and regeneration.

See Figure 2 for a summary of mechanisms underlying warm ischaemia and reperfusion injury.

Underlying mechanisms of hepatic warm ischaemia and reperfusion injury
Figure 2
Underlying mechanisms of hepatic warm ischaemia and reperfusion injury

Pathways recently described are coloured, whereas classic mechanisms are summarized in grey. eNOS, endothelial nitric oxide synthase; ET, endothelin; IL, interleukin; I/R wo hepatectomy, ischaemia/reperfusion without hepatectomy; KC, Kupffer cells; KLF2, Krüppel-like factor 2; LSEC, liver sinusoidal endothelial cells; MMP, matrix metalloproteinase; Nrf2, nuclear factor-erythroid 2-related factor 2; RBP4, retinol-binding protein 4; ROS, reactive oxygen species; TM, thrombomodulin; TNF-α, tumour necrosis factor α.

Figure 2
Underlying mechanisms of hepatic warm ischaemia and reperfusion injury

Pathways recently described are coloured, whereas classic mechanisms are summarized in grey. eNOS, endothelial nitric oxide synthase; ET, endothelin; IL, interleukin; I/R wo hepatectomy, ischaemia/reperfusion without hepatectomy; KC, Kupffer cells; KLF2, Krüppel-like factor 2; LSEC, liver sinusoidal endothelial cells; MMP, matrix metalloproteinase; Nrf2, nuclear factor-erythroid 2-related factor 2; RBP4, retinol-binding protein 4; ROS, reactive oxygen species; TM, thrombomodulin; TNF-α, tumour necrosis factor α.

Controversies

Differences between experimental models and clinical practice

Numerous experimental animal models have been used in the field of warm (and cold) I/R injury. There are many advantages of animal studies: large numbers of animals can be studied, interventional studies can be performed, and tools for targeted manipulation of gene expression provide insight into the function of mediators in hepatic I/R injury. Comparison of the results of animal studies and their extrapolation to human beings is feasible, but with limitations such as differences in ischaemia tolerance, anatomy of the liver of various species, surgical conditions used in clinical practice and those used in the experimental models, and administration, dosage and metabolic breakdown of the drugs under investigation. Importantly, studies performed in small animals are of limited applicability to human beings due to their different size and anatomy of the liver and their faster metabolism. Large animals exhibit greater similarity in their anatomy and physiology to humans; however, their use is restricted by serious logistical and financial difficulties, ethical concerns and limited availability of immunological tools for use in large animal species [36].

Despite the limitations of the experimental animal models, these are the best options to study hepatic I/R, especially considering that the progress of human studies is slow, the majority of human tissues are not routinely accessible for research, and there is very limited opportunity for interventional studies. The clinical application of strategies designed at benchside will depend on the use of experimental models that resemble as much as possible the clinical conditions in which the strategy intends to be applied. As stated above, the pathophysiological mechanisms very much differ depending on the type of ischaemia (cold or warm). In fact, it should be considered that the extent and time of ischaemia, the type of liver submitted to I/R, and the presence of liver regeneration all lead to differences in the mechanisms of hepatic I/R injury and in the effects of therapeutic strategies evaluated [36]. Probably related to these factors, no satisfactory treatment is currently available to prevent warm hepatic I/R injury in the clinical practice. It should be considered that the effectiveness of a certain strategy could be different depending on the surgical conditions evaluated: warm I/R injury itself or partial hepatectomy under warm I/R injury. It would be extremely useful to make a clear distinction between the mechanisms for each surgical situation to design therapies that demonstrate its effectiveness under experimental conditions similar to what happens in clinical practice. This will probably lead to translation of those strategies to clinical practice in the short-term.

Lack of knowledge regarding sinusoidal cells in warm I/R

As stated above, non-parenchymal cells play essential roles in liver function, resulting in being profoundly affected under I/R conditions. Nevertheless, and although recent data unmasked the phenotypic deregulations that LSEC suffer during cold ischaemia and warm reperfusion [4,37], very little is known about sinusoidal cell modifications due to warm ischaemia. An excellent study by Jaeschke et al. [38] demonstrated that Kupffer cells become activated after warm I/R, strongly contributing to liver injury. These data, together with the recruitment of circulating neutrophils after I/R, suggest that the hepatic endothelium may rapidly become dysfunctional upon warm I/R, therefore mediating the inflammatory response. In this regard, a recent study from our team described for the first time that the KLF2-derived vasoprotective pathways are rapidly deregulated in LSEC submitted to warm I/R, leading to endothelial dysfunction development and massive inflammation [39]. Undoubtedly, future studies will clarify the effects of warm I/R on the phenotype and function of LSEC, and desirably also of hepatic stellate cells.

Therapeutic approaches

In the last 2 years, pharmacological therapies with very different targets have predominated in the research on novel strategies to minimize the injurious effects of warm I/R (see Table 2). It is also evident that there is an increasing interest in cellular and surgical strategies. However, and as discussed above, it is important to note that strategies should be developed in experimental models that resemble as much as possible the conditions present in clinical practice, such as the use of intermittent clamping, the combination of PH and I/R injury, and the use of pathological livers such as steatotic or aged. In this sense, few studies have been developed that comply with these characteristics, which can represent an obstacle to the clinical application of other proposed strategies. Accordingly, only one clinical trial analysing a therapy to reduce warm I/R injury has been published in this period of time.

Table 2
Therapeutic approaches against warm I/R injury

AMPK, AMP-activated protein kinase; ATF4, activating transcription factor 4; CHOP, C/EBP (CCAAT/enhancer-binding protein)-homologous protein; eNOS, endothelial nitric oxide synthase; ER, endoplasmic reticulum; FoxO1, forkhead box O1; GPR120, G-protein-coupled receptor 120; GSK3, glycogen synthase kinase 3; HMGB1, high-mobility group protein B1; HO-1, haem oxygenase-1; Hsp70, heat-shock protein 70; IL, interleukin; IPC, ischaemic pre-conditioning; iNOS, inducible nitric oxide synthase; LSEC, liver sinusoidal endothelial cells; MPO, myeloperoxidase; mTOR, mammalian target of rapamycin; NF-κB, nuclear factor κB; NKT, natural killer T-cell; NMP, normothermic machine perfusion; Nrf2, nuclear factor-erythroid 2-related factor 2; PI3K, phosphoinositide 3-kinase; PKA, protein kinase A; PPAR, peroxisome-proliferator-activated receptor; RPC, remote pre-conditioning; SIRT1, sirtuin 1; SOD, superoxide dismutase; STAT, signal transducer and activator of transcription; TLR, Toll-like receptor; TNFα, tumour necrosis factor α; Treg, regulatory T-cell.

(a) Pharmacological strategies
DrugSpeciesExperimental modelWarm ischaemiaEffect
15-deoxy-∆12,14-prostaglandin J2 [76Mouse Partial ischaemia 60 min ↓ Hepatic injury and inflammation; ↑ Nrf2-dependent antioxidant response 
Adiponectin [32] (adipocytokine) Rat Partial ischaemia 60 min ↓ Hepatic injury, inflammation and apoptosis; ↑ AMPK, eNOS 
Ago-miR-146a [77] (a chemically modified miR-146aMouse Partial ischaemia 60 min ↓ Hepatic injury, TLR activation and apoptosis 
Cold-inducible RNA-binding protein (CIRP) blockade [78] (anti-inflammatory) Mouse Partial ischaemia 60 min ↓ Hepatic injury, inflammatory response, apoptosis, nitrosative stress; ↑ survival 
Anti-CD25 monoclonal antibody [79Mouse Partial ischaemia 60 min ↓ Hepatic injury; ↓ inflammatory response, CD4+ T-lymphocytes 
Atorvastatin [80] (vasoprotector) Rat Total ischaemia 60 min ↓ Hepatic injury and inflammation 
Augmenter of liver regeneration [81Mouse Partial ischaemia 90 min ↓ Hepatic injury and apoposis; ↓ recruitment of CD4+ T-cells 
Branched-chain amino acid (BCAA) [82] (Kupffer cell inhibitor) Rat Total ischaemia 30 min ↓ Hepatic injury, inflammation and microcirculatory disorders 
Butyrate [28,83] (four-carbon short-chain fatty acid) Rat Partial ischaemia and partial hepatectomy 30–60 min ↓ Hepatic injury and prevented acetylated histone H3 reduction, inflammatory response, TLR4; inhibition of endotoxin translocation; ↑ Hsp70 
C1 esterase inhibitor [84] (complement inhibitor) Mouse Partial ischaemia and partial hepatectomy 60 min ↓ Hepatic injury; ↑ liver regeneration and survival 
Carbon monoxide [85] (gasotransmitter) Mouse Partial ischaemia 90 min ↓ Hepatic injury; ↑ phosphorylation of Akt, GSK3β 
Carnosic acid [86] (rosemary derivative) Rat Partial ischaemia 45 min ↓ Hepatic injury and p66shc; ↑ SOD and SIRT1 
Carvacrol [87] (antimicrobial) Rat Total ischaemia 30 min ↓ Hepatic injury, apoptosis and oxidative stress; ↑ Akt phosphorylation 
Chloroquine [88] (anti-malaria and autophagy inhibitor) Rat Partial ischaemia 60, 90 min Early phase of reperfusion: ↓ hepatic injury, inflammation and HMGB1. Late phase of reperfusion: ↑ hepatic injury and apoptosis; ↓ autophagy 
Cobalt protoporphyrin [89,90] (HO-1 inductor) Mouse Partial ischaemia 60–90 min ↓ Hepatic injury, inflammation and NF-κB, FoxO1 signalling; ↑ Nrf2, HO-1, PI3K/Akt 
CR2-CD59 [91] (complement inhibitor) Rat Total ischaemia 30 min ↓ Hepatic injury; ↑ regeneration and survival, TNFα, IL-6, STAT3, Akt, ATP recovery 
Dexmedetomidine [92] (sedative) Rat Partial ischaemia 60 min ↓ Hepatic injury and oxidative stress 
Diannexin [93] (microparticle inhibitor) Mouse Partial ischaemia 60 min ↓ Hepatic injury and inflammation; prevents formation of pro-inflammatory and platelet-activating agents 
Diazoxide [94,95] (potassium channel activator) Rat Partial ischaemia 30–60 min ↓ Hepatic injury, inflammation and TLR4, ihibition of endotoxin translocation; ↑ protein kinase Cε 
Dioscin [96] (antioxidant) Rat Partial ischaemia 60 min ↓ Hepatic injury, oxidative stress, inflammation and apoptosis; ↑ survival 
Dipyridamole [97] (equilibrative nucleoside transporter inhibitor) Mouse Partial ischaemia 45 min ↓ Hepatic injury; ↑ adenosine 
Edaravone [98] (free radical scavenger) Rat Partial ischaemia 90 min ↓ Hepatic injury, oxidative stress and lung injury 
Erythropoietin [99] (HO-1 inductor) Mouse Partial ischaemia 90 min ↓ Hepatic injury and apoptosis; ↑ HO-1 
Ethyl pyruvate [100] (anti-inflammatory) Mouse Partial ischaemia 60 min ↓ Hepatic injury, apoptosis, autophagy and HMGB1–TLR4–NF-κB axis 
Exendin 4 [101] (glucagon-like peptide 1 analogue) Mouse Partial ischaemia (steatotic livers) 20 min ↓ Hepatic injury and autophagy; peserves mitochondrial integrity 
Fasting [102Mouse Partial ischaemia 60 min ↓ Hepatic injury, inflammation and HMGB1; ↑ SIRT1, autophagy 
Fibrin-derived peptide Bβ15-42 [103] (leucocyte migration inhibitor) Rat Partial ischaemia 60 min ↓ Hepatic injury, inflammation and HMGB1 
Glucose or lipid emulsion [31] (nutritional supplements) Rat Partial ischaemia + partial hepatectomy (steatotic and non-steatotic livers) 60 min ↓ Hepatic injury; ↑ Liver regeneration, ATP level preservation 
Helium [104Mouse Partial ischaemia 90 min ↓ Hepatic injury; ↑ survival, PI3K/Akt 
Hydrogen sulfide [105,106] (gasotransmitter) Rat, mouse Partial ischaemia + partial hepatectomy 75–90 min ↓ Hepatic injury and miR-34a; ↑ Nrf-2 signalling pathway, pro-survival, anti-apoptotic and anti-inflammatory signals and hepatic regeneration 
Hydrolysed whey peptide [107,108Rat Partial and total ischaemia (steatotic and non-steatotic livers) 30 min ↓ Hepatic injury, apoptosis and inflammation; ↑ NF-κB 
Hydroxytyrosol [109] (phenolic compound) Mouse Partial ischaemia 75 min ↓ Hepatic injury, apoptosis, inflammation and oxidative stress 
Hyperbaric oxygen therapy [110Rat Total ischaemia 30 min ↓ Hepatic injury; ↑ mitochondrial function 
L-α-glycerylphosphorylcholine (GPC) [111] (deacylated phospholipid) Rat Partial ischaemia 60 min ↓ Hepatic injury, NADPH oxidase, MPO and HMGB1; ↓ microcirculatory disorders 
Levosimendan [112,113] (mitochondrial KATP channel opener) Rat Total and partial ischaemia 40 or 60 min ↓ Hepatic injury and apoptosis; ↑ cyclo-oxygenase-1, regulation of oxidative stress, inflammation, NO, and KATP channel, mitochondrial function; improved hepatic microcirculation 
Limonin [114] (antioxidant) Rat Partial ischaemia 45 min ↓ Hepatic injury, oxidative stress, inflammation and TLR-signalling pathway 
Lithium [115Rat Total and partial ischaemia 60–90 min ↓ Hepatic injury; ↓ inflammation and HMGB1 
Losartan [116] (angiotensin receptor antagonist) Mouse Partial ischaemia 60 min ↓ Hepatic injury, apoptosis and inflammation; ↑ PPARγ 
Low-dose LPS [117Mouse Partial ischaemia 90 min ↓ Hepatic injury, apoptosis, inflammation, and ATF4/CHOP pathway 
Low-intensity laser therapy [118Rat Partial ischaemia 45 min ↓ Hepatic injury, oxidative stress and TNF-α 
Melatonin [119] (hormone) Rat Partial ischaemia (steatotic livers) 35 min ↓ Hepatic injury, apoptosis and oxidative stress; ↑ ATP 
miR-370 inhibitor [120Mouse Partial ischaemia 75 min ↓ Hepatic injury; ↓ inflammatory response 
Minocycline [121] (antibiotic) Rat Partial ischaemia 2, 6 and 24 h ↓ Hepatic injury, oxidative stress and inflammatory cytokines; activation of Wnt/β-catenin signalling pathway 
N-Acetylcysteine [122] (antioxidant) Mice Partial ischaemia 40–90 min ↓ Hepatic injury, oxidative stress, ER stress and apoptosis; improvement in structure of sinusoids; ↓ autophagy, apoptosis and JNK phosphorylation 
Platinum nanoparticles [123Mouse Total ischaemia 15 min ↓ Hepatic injury 
Propofol73 [124] (anaesthetic) Rat Partial ischaemia 30, 60, 90 min ↓ Hepatic injury, apoptosis, GSK3β 
Protease-activated receptor 4 antagonist [125] (anti-platelet) Mouse Partial ischaemia 90 min ↓ Hepatic injury, platelets, CD4+ T-cell recruitment and apoptosis 
Rapamycin [126] (mTOR inhibitor) Rat Partial ischaemia 60 min ↓ Hepatic injury; ↑ autophagy, Akt 
Reduced glutathione [127] (antioxidant) Rat Partial ischaemia (young and aged rats) 90 min ↓ Hepatic injury, oxidative stress, TNFα and apoptosis 
Resistin or anti-visfatin antibodies [35] (adipocytokines) Rat Partial ischaemia + partial hepatectomy (steatotic and non-steatotic livers) 60 min ↓ Hepatic injury and visfatin, NAD levels; ↑ liver regeneration 
Rho-kinase inhibitor [128Rat Total ischaemia (steatotic livers) 45 min ↓ Hepatic injury, portal perfusion pressure; ↑ survival 
Riboflavin [129] (vitamin B2Mice Partial ischaemia 60 min ↓ Hepatic injury and inflammation, oxidative stress, eNOS/iNOS and NO levels 
Rosmarinic acid [130] (antioxidant) Rat Partial ischaemia 60 min ↓ Hepatic injury; ↓ oxidative stress, inflammatory response, NF-κB signalling pathway, iNOS, eNOS, NO 
Sevofluorane [131] (anaesthetic) Swine Total ischaemia 40 min ↓ Hepatic injury 
Sevofluorane [132] (anaesthetic) Rat Partial ischaemia 60 min ↓ Hepatic injury and oxidative stress 
Sildenafil [133] (guanylate cyclase inhibitor) Rat Partial ischaemia 90 min ↓ Hepatic injury, apoptosis and inflammation 
Simvastatin [39] (vasoprotector) Rat Partial ischaemia 60 min Early phase of reperfusion: ↓ hepatic injury, LSEC dysfunction. Late phase of reperfusion: ↓ hepatic injury, macrophage and neutrophil infiltration, apoptosis 
Sivelestat sodium hydrate [134] (neutrophil elastase inhibitor) Rat Total ischaemia 30 min ↓ Hepatic injury and neutrophil accumulation 
Thrombomodulin [135] (anti-coagulant) Rat Partial ischaemia + partial hepatectomy 20 min ↓ Hepatic injury, apoptosis and macrophages infiltration; ↑ liver regeneration 
Vasoactive intestinal peptide neuropeptide [136Mouse Partial ischaemia 90 min ↓ Hepatic injury, apoptosis and inflammation; ↑ cAMP/PKA signalling 
α7 Nicotinic acetylcholine receptor activator/agonist [137,138Mouse Partial ischaemia 60 min ↓ Hepatic injury, oxidative stress, inflammation, TNFα and HMGB1; ↑ HO-1, PI3K/Akt, Nrf2 
ω−3 Fatty acid formulation [139,140Mouse Partial ischaemia 60 min ↓ Hepatic injury and inflammation; ↑ GPR120 
(b) Gene and cell therapy strategies
Target gene/cell therapy strategySpeciesExperimental modelWarm ischaemiaEffect
Adipose-derived stem cells [141Mouse Partial ischaemia 15, 20 min ↓ Hepatic injury; ↑ liver regeneration 
ATF6 siRNA [142] (activating transcription factor 6) Mouse Partial ischaemia 90 min ↓ Hepatic injury, ER stress, inflammation; ↑ macrophage TLR4 response, Akt activation 
Bone-marrow-derived mesenchymal stem cells [143Rat Partial ischaemia 60 min ↓ Hepatic injury, oxidative stress and apoptosis 
CD14−/− [144Mouse Partial ischaemia 60 min ↓ Hepatic injury, inflammation and apoptosis 
ENT1−/− [97] (equilibrative nucleoside transporter 1) Mouse Partial ischaemia 45 min ↓ Hepatic injury; ↑ adenosine regulation of Adora2b receptor 
Hepatic stellate cells [145Mouse Partial ischaemia Not reported ↓ Hepatic injury; ↑ Tregs 
Human adipose-derived mesenchymal stem cells [146Mouse Partial ischaemia with or without partial hepatectomy 60 min ↓ Hepatic injury; ↑ liver regeneration and survival 
Interferon regulatory factor 9−/− [147Mouse Partial ischaemia Not reported ↓ Hepatic injury, inflammation and apoptosis; ↑ SIRT1 
Isolated viable mitochondria infusion [148Rat Partial ischaemia 45 min ↓ Hepatic injury and apoptosis 
Long non-coding RNA AK139328 siRNA [149Rat Partial ischaemia 60 min ↓ Hepatic injury, apoptosis and inflammation; ↑ Akt, GSK3β activation, eNOS 
Mesenchymal stem cells [150Rat Total ischaemia 30 min ↓ Hepatic injury and apoptosis 
Mfn2 overexpression [151] (mitochondrial function modulator) Rat Partial ischaemia 90 min ↓ Hepatic injury and apoptosis 
MMP-9−/− [29] (matrix metalloproteinase 9) Mouse Partial ischaemia (steatotic livers) 60 min ↓ Hepatic injury and inflammation; ↑ liver regeneration 
Myeloid PTEN deficiency [152] (phosphatase and tensin homologue deleted on chromosome 10) Mouse Partial ischaemia 90 min ↓ Hepatic injury and inflammation; ↑ IL-10, macrophage differentiation 
Neogenin−/− [153Mouse Partial ischaemia 30 min ↓ Hepatic injury and inflammation 
NLRP3−/− [154] (NOD-like receptor family, pyrin domain-containing 3) Mouse Partial ischaemia 60 min ↓ Hepatic injury, inflammation, oxidative stress, apoptosis and neutrophil infiltration 
TIM-4−/− [155] (T-cell immunoglobulin and mucin 4) Mouse Partial ischaemia 90 min ↓ Hepatic injury and inflammation; ↑ activation of TLR2/4/9-dependent signalling 
TLR4−/− [156] (Toll-like receptor 4) Mouse Partial ischaemia 60 min ↓ Hepatic injury, inflammation and HMGB1 
Toll/interleukin-1 receptor blockade [157Mouse Partial ischaemia 90 min ↓ Hepatic injury, oxidative stress, inflammation and TLR4 
(c) Surgical strategies
StrategySpeciesExperimental model/clinical settingWarm ischaemia timeEffect
IPC [158Rat Partial ischaemia (young and aged rats) 60 min ↓ Hepatic injury; ↑ autophagy, HO-1 
IPC [86,159Rat Partial ischaemia (steatotic and non-steatotic livers) 45–60 min ↓ Hepatic injury and p66shc; ↑ SOD and SIRT1 
IPC [131Swine Total ischaemia 40 min ↓ Hepatic injury 
IPC or GSK3 inhibitor [160Rat Partial ischaemia (young and aged rats) 40 min ↓ Hepatic injury and oxidative stress; ↑ ATP 
RPC [161Rat Partial ischaemia 60 min ↓ Hepatic injury; ↑ microcirculation and blood pressure 
RPC [162Rat Total ischaemia 30 min ↓ Hepatic injury; ↑ survival and HO-1 
RPC [163Rat Partial ischaemia 45 min ↓ Hepatic injury; ↑ HO-1/p38 MAPK-dependent and autophagy 
RPC [164Rat Partial ischaemia 60 min ↓ Hepatic injury, inflammation and NADPH oxidase isoform 2 
(a) Pharmacological strategies
DrugSpeciesExperimental modelWarm ischaemiaEffect
15-deoxy-∆12,14-prostaglandin J2 [76Mouse Partial ischaemia 60 min ↓ Hepatic injury and inflammation; ↑ Nrf2-dependent antioxidant response 
Adiponectin [32] (adipocytokine) Rat Partial ischaemia 60 min ↓ Hepatic injury, inflammation and apoptosis; ↑ AMPK, eNOS 
Ago-miR-146a [77] (a chemically modified miR-146aMouse Partial ischaemia 60 min ↓ Hepatic injury, TLR activation and apoptosis 
Cold-inducible RNA-binding protein (CIRP) blockade [78] (anti-inflammatory) Mouse Partial ischaemia 60 min ↓ Hepatic injury, inflammatory response, apoptosis, nitrosative stress; ↑ survival 
Anti-CD25 monoclonal antibody [79Mouse Partial ischaemia 60 min ↓ Hepatic injury; ↓ inflammatory response, CD4+ T-lymphocytes 
Atorvastatin [80] (vasoprotector) Rat Total ischaemia 60 min ↓ Hepatic injury and inflammation 
Augmenter of liver regeneration [81Mouse Partial ischaemia 90 min ↓ Hepatic injury and apoposis; ↓ recruitment of CD4+ T-cells 
Branched-chain amino acid (BCAA) [82] (Kupffer cell inhibitor) Rat Total ischaemia 30 min ↓ Hepatic injury, inflammation and microcirculatory disorders 
Butyrate [28,83] (four-carbon short-chain fatty acid) Rat Partial ischaemia and partial hepatectomy 30–60 min ↓ Hepatic injury and prevented acetylated histone H3 reduction, inflammatory response, TLR4; inhibition of endotoxin translocation; ↑ Hsp70 
C1 esterase inhibitor [84] (complement inhibitor) Mouse Partial ischaemia and partial hepatectomy 60 min ↓ Hepatic injury; ↑ liver regeneration and survival 
Carbon monoxide [85] (gasotransmitter) Mouse Partial ischaemia 90 min ↓ Hepatic injury; ↑ phosphorylation of Akt, GSK3β 
Carnosic acid [86] (rosemary derivative) Rat Partial ischaemia 45 min ↓ Hepatic injury and p66shc; ↑ SOD and SIRT1 
Carvacrol [87] (antimicrobial) Rat Total ischaemia 30 min ↓ Hepatic injury, apoptosis and oxidative stress; ↑ Akt phosphorylation 
Chloroquine [88] (anti-malaria and autophagy inhibitor) Rat Partial ischaemia 60, 90 min Early phase of reperfusion: ↓ hepatic injury, inflammation and HMGB1. Late phase of reperfusion: ↑ hepatic injury and apoptosis; ↓ autophagy 
Cobalt protoporphyrin [89,90] (HO-1 inductor) Mouse Partial ischaemia 60–90 min ↓ Hepatic injury, inflammation and NF-κB, FoxO1 signalling; ↑ Nrf2, HO-1, PI3K/Akt 
CR2-CD59 [91] (complement inhibitor) Rat Total ischaemia 30 min ↓ Hepatic injury; ↑ regeneration and survival, TNFα, IL-6, STAT3, Akt, ATP recovery 
Dexmedetomidine [92] (sedative) Rat Partial ischaemia 60 min ↓ Hepatic injury and oxidative stress 
Diannexin [93] (microparticle inhibitor) Mouse Partial ischaemia 60 min ↓ Hepatic injury and inflammation; prevents formation of pro-inflammatory and platelet-activating agents 
Diazoxide [94,95] (potassium channel activator) Rat Partial ischaemia 30–60 min ↓ Hepatic injury, inflammation and TLR4, ihibition of endotoxin translocation; ↑ protein kinase Cε 
Dioscin [96] (antioxidant) Rat Partial ischaemia 60 min ↓ Hepatic injury, oxidative stress, inflammation and apoptosis; ↑ survival 
Dipyridamole [97] (equilibrative nucleoside transporter inhibitor) Mouse Partial ischaemia 45 min ↓ Hepatic injury; ↑ adenosine 
Edaravone [98] (free radical scavenger) Rat Partial ischaemia 90 min ↓ Hepatic injury, oxidative stress and lung injury 
Erythropoietin [99] (HO-1 inductor) Mouse Partial ischaemia 90 min ↓ Hepatic injury and apoptosis; ↑ HO-1 
Ethyl pyruvate [100] (anti-inflammatory) Mouse Partial ischaemia 60 min ↓ Hepatic injury, apoptosis, autophagy and HMGB1–TLR4–NF-κB axis 
Exendin 4 [101] (glucagon-like peptide 1 analogue) Mouse Partial ischaemia (steatotic livers) 20 min ↓ Hepatic injury and autophagy; peserves mitochondrial integrity 
Fasting [102Mouse Partial ischaemia 60 min ↓ Hepatic injury, inflammation and HMGB1; ↑ SIRT1, autophagy 
Fibrin-derived peptide Bβ15-42 [103] (leucocyte migration inhibitor) Rat Partial ischaemia 60 min ↓ Hepatic injury, inflammation and HMGB1 
Glucose or lipid emulsion [31] (nutritional supplements) Rat Partial ischaemia + partial hepatectomy (steatotic and non-steatotic livers) 60 min ↓ Hepatic injury; ↑ Liver regeneration, ATP level preservation 
Helium [104Mouse Partial ischaemia 90 min ↓ Hepatic injury; ↑ survival, PI3K/Akt 
Hydrogen sulfide [105,106] (gasotransmitter) Rat, mouse Partial ischaemia + partial hepatectomy 75–90 min ↓ Hepatic injury and miR-34a; ↑ Nrf-2 signalling pathway, pro-survival, anti-apoptotic and anti-inflammatory signals and hepatic regeneration 
Hydrolysed whey peptide [107,108Rat Partial and total ischaemia (steatotic and non-steatotic livers) 30 min ↓ Hepatic injury, apoptosis and inflammation; ↑ NF-κB 
Hydroxytyrosol [109] (phenolic compound) Mouse Partial ischaemia 75 min ↓ Hepatic injury, apoptosis, inflammation and oxidative stress 
Hyperbaric oxygen therapy [110Rat Total ischaemia 30 min ↓ Hepatic injury; ↑ mitochondrial function 
L-α-glycerylphosphorylcholine (GPC) [111] (deacylated phospholipid) Rat Partial ischaemia 60 min ↓ Hepatic injury, NADPH oxidase, MPO and HMGB1; ↓ microcirculatory disorders 
Levosimendan [112,113] (mitochondrial KATP channel opener) Rat Total and partial ischaemia 40 or 60 min ↓ Hepatic injury and apoptosis; ↑ cyclo-oxygenase-1, regulation of oxidative stress, inflammation, NO, and KATP channel, mitochondrial function; improved hepatic microcirculation 
Limonin [114] (antioxidant) Rat Partial ischaemia 45 min ↓ Hepatic injury, oxidative stress, inflammation and TLR-signalling pathway 
Lithium [115Rat Total and partial ischaemia 60–90 min ↓ Hepatic injury; ↓ inflammation and HMGB1 
Losartan [116] (angiotensin receptor antagonist) Mouse Partial ischaemia 60 min ↓ Hepatic injury, apoptosis and inflammation; ↑ PPARγ 
Low-dose LPS [117Mouse Partial ischaemia 90 min ↓ Hepatic injury, apoptosis, inflammation, and ATF4/CHOP pathway 
Low-intensity laser therapy [118Rat Partial ischaemia 45 min ↓ Hepatic injury, oxidative stress and TNF-α 
Melatonin [119] (hormone) Rat Partial ischaemia (steatotic livers) 35 min ↓ Hepatic injury, apoptosis and oxidative stress; ↑ ATP 
miR-370 inhibitor [120Mouse Partial ischaemia 75 min ↓ Hepatic injury; ↓ inflammatory response 
Minocycline [121] (antibiotic) Rat Partial ischaemia 2, 6 and 24 h ↓ Hepatic injury, oxidative stress and inflammatory cytokines; activation of Wnt/β-catenin signalling pathway 
N-Acetylcysteine [122] (antioxidant) Mice Partial ischaemia 40–90 min ↓ Hepatic injury, oxidative stress, ER stress and apoptosis; improvement in structure of sinusoids; ↓ autophagy, apoptosis and JNK phosphorylation 
Platinum nanoparticles [123Mouse Total ischaemia 15 min ↓ Hepatic injury 
Propofol73 [124] (anaesthetic) Rat Partial ischaemia 30, 60, 90 min ↓ Hepatic injury, apoptosis, GSK3β 
Protease-activated receptor 4 antagonist [125] (anti-platelet) Mouse Partial ischaemia 90 min ↓ Hepatic injury, platelets, CD4+ T-cell recruitment and apoptosis 
Rapamycin [126] (mTOR inhibitor) Rat Partial ischaemia 60 min ↓ Hepatic injury; ↑ autophagy, Akt 
Reduced glutathione [127] (antioxidant) Rat Partial ischaemia (young and aged rats) 90 min ↓ Hepatic injury, oxidative stress, TNFα and apoptosis 
Resistin or anti-visfatin antibodies [35] (adipocytokines) Rat Partial ischaemia + partial hepatectomy (steatotic and non-steatotic livers) 60 min ↓ Hepatic injury and visfatin, NAD levels; ↑ liver regeneration 
Rho-kinase inhibitor [128Rat Total ischaemia (steatotic livers) 45 min ↓ Hepatic injury, portal perfusion pressure; ↑ survival 
Riboflavin [129] (vitamin B2Mice Partial ischaemia 60 min ↓ Hepatic injury and inflammation, oxidative stress, eNOS/iNOS and NO levels 
Rosmarinic acid [130] (antioxidant) Rat Partial ischaemia 60 min ↓ Hepatic injury; ↓ oxidative stress, inflammatory response, NF-κB signalling pathway, iNOS, eNOS, NO 
Sevofluorane [131] (anaesthetic) Swine Total ischaemia 40 min ↓ Hepatic injury 
Sevofluorane [132] (anaesthetic) Rat Partial ischaemia 60 min ↓ Hepatic injury and oxidative stress 
Sildenafil [133] (guanylate cyclase inhibitor) Rat Partial ischaemia 90 min ↓ Hepatic injury, apoptosis and inflammation 
Simvastatin [39] (vasoprotector) Rat Partial ischaemia 60 min Early phase of reperfusion: ↓ hepatic injury, LSEC dysfunction. Late phase of reperfusion: ↓ hepatic injury, macrophage and neutrophil infiltration, apoptosis 
Sivelestat sodium hydrate [134] (neutrophil elastase inhibitor) Rat Total ischaemia 30 min ↓ Hepatic injury and neutrophil accumulation 
Thrombomodulin [135] (anti-coagulant) Rat Partial ischaemia + partial hepatectomy 20 min ↓ Hepatic injury, apoptosis and macrophages infiltration; ↑ liver regeneration 
Vasoactive intestinal peptide neuropeptide [136Mouse Partial ischaemia 90 min ↓ Hepatic injury, apoptosis and inflammation; ↑ cAMP/PKA signalling 
α7 Nicotinic acetylcholine receptor activator/agonist [137,138Mouse Partial ischaemia 60 min ↓ Hepatic injury, oxidative stress, inflammation, TNFα and HMGB1; ↑ HO-1, PI3K/Akt, Nrf2 
ω−3 Fatty acid formulation [139,140Mouse Partial ischaemia 60 min ↓ Hepatic injury and inflammation; ↑ GPR120 
(b) Gene and cell therapy strategies
Target gene/cell therapy strategySpeciesExperimental modelWarm ischaemiaEffect
Adipose-derived stem cells [141Mouse Partial ischaemia 15, 20 min ↓ Hepatic injury; ↑ liver regeneration 
ATF6 siRNA [142] (activating transcription factor 6) Mouse Partial ischaemia 90 min ↓ Hepatic injury, ER stress, inflammation; ↑ macrophage TLR4 response, Akt activation 
Bone-marrow-derived mesenchymal stem cells [143Rat Partial ischaemia 60 min ↓ Hepatic injury, oxidative stress and apoptosis 
CD14−/− [144Mouse Partial ischaemia 60 min ↓ Hepatic injury, inflammation and apoptosis 
ENT1−/− [97] (equilibrative nucleoside transporter 1) Mouse Partial ischaemia 45 min ↓ Hepatic injury; ↑ adenosine regulation of Adora2b receptor 
Hepatic stellate cells [145Mouse Partial ischaemia Not reported ↓ Hepatic injury; ↑ Tregs 
Human adipose-derived mesenchymal stem cells [146Mouse Partial ischaemia with or without partial hepatectomy 60 min ↓ Hepatic injury; ↑ liver regeneration and survival 
Interferon regulatory factor 9−/− [147Mouse Partial ischaemia Not reported ↓ Hepatic injury, inflammation and apoptosis; ↑ SIRT1 
Isolated viable mitochondria infusion [148Rat Partial ischaemia 45 min ↓ Hepatic injury and apoptosis 
Long non-coding RNA AK139328 siRNA [149Rat Partial ischaemia 60 min ↓ Hepatic injury, apoptosis and inflammation; ↑ Akt, GSK3β activation, eNOS 
Mesenchymal stem cells [150Rat Total ischaemia 30 min ↓ Hepatic injury and apoptosis 
Mfn2 overexpression [151] (mitochondrial function modulator) Rat Partial ischaemia 90 min ↓ Hepatic injury and apoptosis 
MMP-9−/− [29] (matrix metalloproteinase 9) Mouse Partial ischaemia (steatotic livers) 60 min ↓ Hepatic injury and inflammation; ↑ liver regeneration 
Myeloid PTEN deficiency [152] (phosphatase and tensin homologue deleted on chromosome 10) Mouse Partial ischaemia 90 min ↓ Hepatic injury and inflammation; ↑ IL-10, macrophage differentiation 
Neogenin−/− [153Mouse Partial ischaemia 30 min ↓ Hepatic injury and inflammation 
NLRP3−/− [154] (NOD-like receptor family, pyrin domain-containing 3) Mouse Partial ischaemia 60 min ↓ Hepatic injury, inflammation, oxidative stress, apoptosis and neutrophil infiltration 
TIM-4−/− [155] (T-cell immunoglobulin and mucin 4) Mouse Partial ischaemia 90 min ↓ Hepatic injury and inflammation; ↑ activation of TLR2/4/9-dependent signalling 
TLR4−/− [156] (Toll-like receptor 4) Mouse Partial ischaemia 60 min ↓ Hepatic injury, inflammation and HMGB1 
Toll/interleukin-1 receptor blockade [157Mouse Partial ischaemia 90 min ↓ Hepatic injury, oxidative stress, inflammation and TLR4 
(c) Surgical strategies
StrategySpeciesExperimental model/clinical settingWarm ischaemia timeEffect
IPC [158Rat Partial ischaemia (young and aged rats) 60 min ↓ Hepatic injury; ↑ autophagy, HO-1 
IPC [86,159Rat Partial ischaemia (steatotic and non-steatotic livers) 45–60 min ↓ Hepatic injury and p66shc; ↑ SOD and SIRT1 
IPC [131Swine Total ischaemia 40 min ↓ Hepatic injury 
IPC or GSK3 inhibitor [160Rat Partial ischaemia (young and aged rats) 40 min ↓ Hepatic injury and oxidative stress; ↑ ATP 
RPC [161Rat Partial ischaemia 60 min ↓ Hepatic injury; ↑ microcirculation and blood pressure 
RPC [162Rat Total ischaemia 30 min ↓ Hepatic injury; ↑ survival and HO-1 
RPC [163Rat Partial ischaemia 45 min ↓ Hepatic injury; ↑ HO-1/p38 MAPK-dependent and autophagy 
RPC [164Rat Partial ischaemia 60 min ↓ Hepatic injury, inflammation and NADPH oxidase isoform 2 

J.G.-S. and C.P. acknowledge the current and former members of their laboratories for their valuable contributions.

FUNDING

Research from the groups of J.G.-S. and C.P. is supported by the Instituto de Salud Carlos III [grant number FIS PI14/00029 to (J.G.-S.)], the Spanish Ministry of Economy and Competitiveness [grant number SAF2012-31238 to (C.P.)], and the European Funds FEDER. CIBEREHD is funded by the Instituto de Salud Carlos III.

Abbreviations

     
  • B7-H1

    B7 homologue 1

  •  
  • DAMP

    damage-associated molecular pattern

  •  
  • eNOS

    endothelial nitric oxide synthase

  •  
  • HDmiR

    hepatocyte-derived miRNA

  •  
  • I/R

    ischaemia/reperfusion

  •  
  • IRF

    interferon-regulatory factor

  •  
  • KLF2

    Krüppel-like factor 2

  •  
  • LSEC

    liver sinusoidal endothelial cells

  •  
  • MAPK

    mitogen-activated protein kinase

  •  
  • MMP

    matrix metalloproteinase

  •  
  • NMP

    normothermic machine perfusion

  •  
  • Nrf2

    nuclear factor-erythroid 2-related factor 2

  •  
  • PAMP

    pathogen-associated molecular pattern

  •  
  • PH

    partial hepatectomy

  •  
  • RBP4

    retinol-binding protein 4

  •  
  • TLR

    Toll-like receptor

References

References
1
de Rougemont
 
O.
Lehmann
 
K.
Clavien
 
P.A.
 
Preconditioning, organ preservation, and postconditioning to prevent ischemia–reperfusion injury to the liver
Liver Transpl.
2009
, vol. 
15
 (pg. 
1172
-
1182
)
[PubMed]
2
Montalvo-Jave
 
E.E.
Escalante-Tattersfield
 
T.
Ortega-Salgado
 
J.A.
Pina
 
E.
Geller
 
D.A.
 
Factors in the pathophysiology of the liver ischemia–reperfusion injury
J. Surg. Res.
2008
, vol. 
147
 (pg. 
153
-
159
)
[PubMed]
3
Rauen
 
U.
Polzar
 
B.
Stephan
 
H.
Mannherz
 
H.G.
de Groot
 
H.
 
Cold-induced apoptosis in cultured hepatocytes and liver endothelial cells: mediation by reactive oxygen species
FASEB J.
1999
, vol. 
13
 (pg. 
155
-
168
)
[PubMed]
4
Russo
 
L.
Gracia-Sancho
 
J.
Garcia-Caldero
 
H.
Marrone
 
G.
Garcia-Pagan
 
J.C.
Garcia-Cardena
 
G.
Bosch
 
J.
 
Addition of simvastatin to cold storage solution prevents endothelial dysfunction in explanted rat livers
Hepatology
2012
, vol. 
55
 (pg. 
921
-
930
)
[PubMed]
5
Stolz
 
D.B.
Ross
 
M.A.
Ikeda
 
A.
Tomiyama
 
K.
Kaizu
 
T.
Geller
 
D.A.
Murase
 
N.
 
Sinusoidal endothelial cell repopulation following ischemia/reperfusion injury in rat liver transplantation
Hepatology
2007
, vol. 
46
 (pg. 
1464
-
1475
)
[PubMed]
6
Gracia-Sancho
 
J.
Villarreal
 
G.
Zhang
 
Y.
Yu
 
J.X.
Liu
 
Y.
Tullius
 
S.G.
Garcia-Cardena
 
G.
 
Flow cessation triggers endothelial dysfunction during organ cold storage conditions: strategies for pharmacologic intervention
Transplantation
2010
, vol. 
90
 (pg. 
142
-
149
)
[PubMed]
7
Shen
 
X.D.
Ke
 
B.
Zhai
 
Y.
Gao
 
F.
Tsuchihashi
 
S.
Lassman
 
C.R.
Busuttil
 
R.W.
Kupiec-Weglinski
 
J.W.
 
Absence of Toll-like receptor 4 (TLR4) signaling in the donor organ reduces ischemia and reperfusion injury in a murine liver transplantation model
Liver Transpl.
2007
, vol. 
13
 (pg. 
1435
-
1443
)
[PubMed]
8
Jimenez-Castro
 
M.B.
Elias-Miro
 
M.
Mendes-Braz
 
M.
Lemoine
 
A.
Rimola
 
A.
Rodes
 
J.
Casillas-Ramírez
 
A.
Peralta
 
C.
 
Tauroursodeoxycholic acid affects PPARγ and TLR4 in steatotic liver transplantation
Am. J. Transplant.
2012
, vol. 
12
 (pg. 
3257
-
3271
)
[PubMed]
9
Minor
 
T.
Stegemann
 
J.
Hirner
 
A.
Koetting
 
M.
 
Impaired autophagic clearance after cold preservation of fatty livers correlates with tissue necrosis upon reperfusion and is reversed by hypothermic reconditioning
Liver Transpl.
2009
, vol. 
15
 (pg. 
798
-
805
)
[PubMed]
10
Farid
 
W.R.
Pan
 
Q.
van der Meer
 
A.J.
de Ruiter
 
P.E.
Ramakrishnaiah
 
V.
de Jonge
 
J.
Kwekkeboom
 
J.
Janssen
 
H.L.
Metselaar
 
H.J.
Tilanus
 
H.W.
, et al 
Hepatocyte-derived microRNAs as serum biomarkers of hepatic injury and rejection after liver transplantation
Liver Transpl.
2012
, vol. 
18
 (pg. 
290
-
297
)
[PubMed]
11
Kim
 
K.H.
Dhupar
 
R.
Ueki
 
S.
Cardinal
 
J.
Pan
 
P.
Cao
 
Z.
Cho
 
S.W.
Murase
 
N.
Tsung
 
A.
Geller
 
D.A.
 
Donor graft interferon regulatory factor-1 gene transfer worsens liver transplant ischemia/reperfusion injury
Surgery
2009
, vol. 
146
 (pg. 
181
-
189
)
[PubMed]
12
Ueki
 
S.
Dhupar
 
R.
Cardinal
 
J.
Tsung
 
A.
Yoshida
 
J.
Ozaki
 
K.S.
Klune
 
J.R.
Murase
 
N.
Geller
 
D.A.
 
Critical role of interferon regulatory factor-1 in murine liver transplant ischemia reperfusion injury
Hepatology
2010
, vol. 
51
 (pg. 
1692
-
1701
)
[PubMed]
13
Ueki
 
S.
Castellaneta
 
A.
Yoshida
 
O.
Ozaki
 
K.
Zhang
 
M.
Kimura
 
S.
Isse
 
K.
Ross
 
M.
Shao
 
L.
Stolz
 
D.B.
Thomson
 
A.W.
Demetris
 
A.J.
Geller
 
D.A.
Murase
 
N.
 
Hepatic B7 homolog 1 expression is essential for controlling cold ischemia/reperfusion injury after mouse liver transplantation
Hepatology
2011
, vol. 
54
 (pg. 
216
-
228
)
[PubMed]
14
Van der Hoeven
 
J.A.
Lindell
 
S.
van
 
S.R.
Molema
 
G.
Ter Horst
 
G.J.
Southard
 
J.H.
Ploeg
 
R.J.
 
Donor brain death reduces survival after transplantation in rat livers preserved for 20 hr
Transplantation.
2001
, vol. 
72
 (pg. 
1632
-
1636
)
[PubMed]
15
Jimenez-Castro
 
M.B.
Merono
 
N.
Mendes-Braz
 
M.
Gracia-Sancho
 
J.
Martinez-Carreres
 
L.
Cornide-Petronio
 
M.E.
Casillas-Ramírez
 
A.
Rodes
 
J.
Peralta
 
C.
 
The effect of brain death in rat steatotic and non-steatotic liver transplantation with previous ischemic preconditioning
J. Hepatol.
2014
, vol. 
62
 (pg. 
83
-
91
)
[PubMed]
16
Vollmar
 
B.
Glasz
 
J.
Leiderer
 
R.
Post
 
S.
Menger
 
M.D.
 
Hepatic microcirculatory perfusion failure is a determinant of liver dysfunction in warm ischemia–reperfusion
Am. J. Pathol.
1994
, vol. 
145
 (pg. 
1421
-
1431
)
[PubMed]
17
Fondevila
 
C.
Hessheimer
 
A.J.
Maathuis
 
M.H.
Munoz
 
J.
Taura
 
P.
Calatayud
 
D.
Leuvenink
 
H.
Rimola
 
A.
Ploeg
 
R.J.
Garcia-Valdecasas
 
J.C.
 
Superior preservation of DCD livers with continuous normothermic perfusion
Ann. Surg.
2011
, vol. 
254
 (pg. 
1000
-
1007
)
[PubMed]
18
Sutton
 
M.E.
op den Dries
 
S.
Karimian
 
N.
Weeder
 
P.D.
de Boer
 
M.T.
Wiersema-Buist
 
J.
Gouw
 
A.S.
Leuvenink
 
H.G.
Lisman
 
T.
Porte
 
R.J.
 
Criteria for viability assessment of discarded human donor livers during ex vivo normothermic machine perfusion
PLoS ONE
2014
, vol. 
9
 pg. 
e110642
 
[PubMed]
19
op den Dries
 
S.
Karimian
 
N.
Sutton
 
M.E.
Westerkamp
 
A.C.
Nijsten
 
M.W.
Gouw
 
A.S.
Wiersema-Buist
 
J.
Lisman
 
T.
Leuvenink
 
H.G.
Porte
 
R.J.
 
Ex vivo normothermic machine perfusion and viability testing of discarded human donor livers
Am. J. Transplant.
2013
, vol. 
13
 (pg. 
1327
-
1335
)
[PubMed]
20
Barrou
 
B.
Billault
 
C.
Nicolas-Robin
 
A.
 
The use of extracorporeal membranous oxygenation in donors after cardiac death
Curr. Opin. Organ Transplant.
2013
, vol. 
18
 (pg. 
148
-
153
)
[PubMed]
21
Valero
 
R.
Cabrer
 
C.
Oppenheimer
 
F.
Trias
 
E.
Sanchez-Ibanez
 
J.
De Cabo
 
F.M.
Navarro
 
A.
Paredes
 
D.
Alcaraz
 
A.
Gutierrez
 
R.
Manyalich
 
M.
 
Normothermic recirculation reduces primary graft dysfunction of kidneys obtained from non-heart-beating donors
Transpl. Int.
2000
, vol. 
13
 (pg. 
303
-
310
)
[PubMed]
22
Fondevila
 
C.
Hessheimer
 
A.J.
Ruiz
 
A.
Calatayud
 
D.
Ferrer
 
J.
Charco
 
R.
Fuster
 
J.
Navasa
 
M.
Rimola
 
A.
Taura
 
P.
, et al 
Liver transplant using donors after unexpected cardiac death: novel preservation protocol and acceptance criteria
Am. J. Transplant.
2007
, vol. 
7
 (pg. 
1849
-
1855
)
[PubMed]
23
Butler
 
A.J.
Randle
 
L.V.
Watson
 
C.J.
 
Normothermic regional perfusion for donation after circulatory death without prior heparinization
Transplantation
2014
, vol. 
97
 (pg. 
1272
-
1278
)
[PubMed]
24
Oniscu
 
G.C.
Randle
 
L.V.
Muiesan
 
P.
Butler
 
A.J.
Currie
 
I.S.
Perera
 
M.T.
Forsythe
 
J.L.
Watson
 
C.J.
 
In situ normothermic regional perfusion for controlled donation after circulatory death: the United Kingdom experience
Am. J. Transplant.
2014
, vol. 
14
 (pg. 
2846
-
2854
)
[PubMed]
25
Fontes
 
P.
Lopez
 
R.
van der Plaats
 
A.
Vodovotz
 
Y.
Minervini
 
M.
Scott
 
V.
Soltys
 
K.
Shiva
 
S.
Paranjpe
 
S.
Sadowsky
 
D.
, et al 
Liver preservation with machine perfusion and a newly developed cell-free oxygen carrier solution under subnormothermic conditions
Am. J. Transplant.
2015
, vol. 
15
 (pg. 
381
-
394
)
[PubMed]
26
Jaeschke
 
H.
 
Mechanisms of reperfusion injury after warm ischemia of the liver
J. Hepatobiliary Pancreat. Surg.
1998
, vol. 
5
 (pg. 
402
-
408
)
[PubMed]
27
Martens
 
J.C.
Keilhoff
 
G.
Halangk
 
W.
Wartmann
 
T.
Gardemann
 
A.
Page
 
I.
Schild
 
L.
 
Lipidomic analysis of molecular cardiolipin species in livers exposed to ischemia/reperfusion
Mol. Cell. Biochem.
2015
, vol. 
400
 (pg. 
253
-
263
)
[PubMed]
28
Sun
 
J.
Wu
 
Q.
Sun
 
H.
Qiao
 
Y.
 
Inhibition of histone deacetylase by butyrate protects rat liver from ischemic reperfusion injury
Int. J. Mol. Sci.
2014
, vol. 
15
 (pg. 
21069
-
21079
)
[PubMed]
29
Kato
 
H.
Kuriyama
 
N.
Duarte
 
S.
Clavien
 
P.A.
Busuttil
 
R.W.
Coito
 
A.J.
 
MMP-9 deficiency shelters endothelial PECAM-1 expression and enhances regeneration of steatotic livers after ischemia and reperfusion injury
J. Hepatol.
2014
, vol. 
60
 (pg. 
1032
-
1039
)
[PubMed]
30
Garcia-Irigoyen
 
O.
Carotti
 
S.
Latasa
 
M.U.
Uriarte
 
I.
Fernandez-Barrena
 
M.G.
Elizalde
 
M.
Urtasun
 
R.
Vespasiani-Gentilucci
 
U.
Morini
 
S.
Banales
 
J.M.
, et al 
Matrix metalloproteinase-10 expression is induced during hepatic injury and plays a fundamental role in liver tissue repair
Liver Int.
2014
, vol. 
34
 (pg. 
e257
-
e270
)
[PubMed]
31
Mendes-Braz
 
M.
Elias-Miro
 
M.
Kleuser
 
B.
Fayyaz
 
S.
Jimenez-Castro
 
M.B.
Massip-Salcedo
 
M.
Gracia-Sancho
 
J.
Ramalho
 
F.S.
Rodes
 
J.
Peralta
 
C.
 
The effects of glucose and lipids in steatotic and non-steatotic livers in conditions of partial hepatectomy under ischaemia–reperfusion
Liver Int.
2014
, vol. 
34
 (pg. 
e271
-
e289
)
[PubMed]
32
Zhang
 
C.
Liao
 
Y.
Li
 
Q.
Chen
 
M.
Zhao
 
Q.
Deng
 
R.
Wu
 
C.
Yang
 
A.
Guo
 
Z.
Wang
 
D.
He
 
X.
 
Recombinant adiponectin ameliorates liver ischemia reperfusion injury via activating the AMPK/eNOS pathway
PLoS ONE
2013
, vol. 
8
 pg. 
e66382
 
[PubMed]
33
Massip-Salcedo
 
M.
Zaouali
 
M.A.
Padrissa-Altes
 
S.
Casillas-Ramírez
 
A.
Rodes
 
J.
Rosello-Catafau
 
J.
Peralta
 
C.
 
Activation of peroxisome proliferator-activated receptor-α inhibits the injurious effects of adiponectin in rat steatotic liver undergoing ischemia–reperfusion
Hepatology
2008
, vol. 
47
 (pg. 
461
-
472
)
[PubMed]
34
Elias-Miro
 
M.
Massip-Salcedo
 
M.
Raila
 
J.
Schweigert
 
F.
Mendes-Braz
 
M.
Ramalho
 
F.
Jimenez-Castro
 
M.B.
Casillas-Ramírez
 
A.
Bermudo
 
R.
Rimola
 
A.
, et al 
Retinol binding protein 4 and retinol in steatotic and nonsteatotic rat livers in the setting of partial hepatectomy under ischemia/reperfusion
Liver Transpl.
2012
, vol. 
18
 (pg. 
1198
-
1208
)
[PubMed]
35
Elias-Miro
 
M.
Mendes-Braz
 
M.
Cereijo
 
R.
Villarroya
 
F.
Jimenez-Castro
 
M.B.
Gracia-Sancho
 
J.
Guixe-Muntet
 
S.
Massip-Salcedo
 
M.
Domingo
 
J.C.
Bermudo
 
R.
, et al 
Resistin and visfatin in steatotic and non-steatotic livers in the setting of partial hepatectomy under ischemia–reperfusion
J. Hepatol.
2014
, vol. 
60
 (pg. 
87
-
95
)
[PubMed]
36
Mendes-Braz
 
M.
Elias-Miro
 
M.
Jimenez-Castro
 
M.B.
Casillas-Ramírez
 
A.
Ramalho
 
F.S.
Peralta
 
C.
 
The current state of knowledge of hepatic ischemia–reperfusion injury based on its study in experimental models
J. Biomed. Biotechnol.
2012
, vol. 
2012
 pg. 
298657
 
[PubMed]
37
Hide
 
D.
Ortega-Ribera
 
M.
Fernandez-Iglesias
 
A.
Fondevila
 
C.
Salvado
 
M.J.
Arola
 
L.
Garcia-Pagan
 
J.C.
Mancini
 
A.
Bosch
 
J.
Gracia-Sancho
 
J.
 
A novel form of the human manganese superoxide dismutase protects rat and human livers undergoing ischemia and reperfusion injuries
Clin. Sci.
2014
, vol. 
127
 (pg. 
527
-
537
)
[PubMed]
38
Jaeschke
 
H.
Bautista
 
A.P.
Spolarics
 
Z.
Spitzer
 
J.J.
 
Superoxide generation by neutrophils and Kupffer cells during in vivo reperfusion after hepatic ischemia in rats
J. Leukoc. Biol.
1992
, vol. 
52
 (pg. 
377
-
382
)
[PubMed]
39
Hide
 
D.
Ortega-Ribera
 
M.
Vila
 
S.
Peralta
 
C.
Garcia-Pagan
 
J.C.
Bosch
 
J.
Gracia-Sancho
 
J.
 
Warm ischemia and reperfusion causes liver microcirculatory injury and acute endothelial dysfunction: simvastatin prevents these deleterious events
Hepatology
2014
, vol. 
60
 pg. 
522A
 
40
Jimenez-Castro
 
M.B.
Casillas-Ramírez
 
A.
Mendes-Braz
 
M.
Massip-Salcedo
 
M.
Gracia-Sancho
 
J.
Elias-Miro
 
M.
Rodes
 
J.
Peralta
 
C.
 
Adiponectin and resistin protect steatotic livers undergoing transplantation
J. Hepatol.
2013
, vol. 
59
 (pg. 
1208
-
1214
)
[PubMed]
41
Chen
 
G.
Zhang
 
L.
Chen
 
L.
Wang
 
H.
Zhang
 
Y.
Bie
 
P.
 
Role of integrin αvβ6 in the pathogenesis of ischemia-related biliary fibrosis after liver transplantation
Transplantation
2013
, vol. 
95
 (pg. 
1092
-
1099
)
[PubMed]
42
Andria
 
B.
Bracco
 
A.
Attanasio
 
C.
Castaldo
 
S.
Cerrito
 
M.G.
Cozzolino
 
S.
Di Napoli
 
D.
Giovannoni
 
R.
Mancini
 
A.
Musumeci
 
A.
, et al 
Biliverdin protects against liver ischemia reperfusion injury in swine
PLoS ONE
2013
, vol. 
8
 pg. 
e69972
 
[PubMed]
43
Tiriveedhi
 
V.
Upadhya
 
G.A.
Busch
 
R.A.
Gunter
 
K.L.
Dines
 
J.N.
Knolhoff
 
B.L.
Jia
 
J.
Sarma
 
N.J.
Ramachandran
 
S.
Anderson
 
C.D.
, et al 
Protective role of bortezomib in steatotic liver ischemia/reperfusion injury through abrogation of MMP activation and YKL-40 expression
Transpl. Immunol.
2014
, vol. 
30
 (pg. 
93
-
98
)
[PubMed]
44
Aguilar-Melero
 
P.
Luque
 
A.
Machuca
 
M.M.
Pérez de Obanos
 
M.P.
Navarrete
 
R.
Rodríguez-García
 
I.C.
Briceno
 
J.
Iniguez
 
M.
Ruiz
 
J.
Prieto
 
J.
, et al 
Cardiotrophin-1 reduces ischemia/reperfusion injury during liver transplant
J. Surg. Res.
2013
, vol. 
181
 (pg. 
e83
-
e91
)
[PubMed]
45
Miyazawa
 
K.
Miyagi
 
S.
Maida
 
K.
Murakami
 
K.
Fujio
 
A.
Kashiwadate
 
T.
Nakanishi
 
W.
Hara
 
Y.
Nakanishi
 
C.
Yamaya
 
H.
, et al 
Edaravone, a free radical scavenger, improves the graft viability on liver transplantation from non-heart-beating donors in pigs
Transplant. Proc.
2014
, vol. 
46
 (pg. 
1090
-
1094
)
[PubMed]
46
Lehne
 
K.
Nobiling
 
R.
 
Metabolic preconditioning with fructose prior to organ recovery attenuates ischemia–reperfusion injury in the isolated perfused rat liver
Scand. J. Gastroenterol.
2013
, vol. 
48
 (pg. 
218
-
224
)
[PubMed]
47
Hori
 
T.
Gardner
 
L.B.
Hata
 
T.
Chen
 
F.
Baine
 
A.M.
Uemoto
 
S.
Nguyen
 
J.H.
 
Pretreatment of liver grafts in vivo by γ-aminobutyric acid receptor regulation reduces cold ischemia/warm reperfusion injury in rat
Ann. Transplant.
2013
, vol. 
18
 (pg. 
299
-
313
)
[PubMed]
48
Chen
 
L.
Chen
 
G.
Guo
 
Y.
Liu
 
L.
Xiao
 
L.
Fan
 
W.
Shi
 
B.
Qian
 
Y.
 
Ketanserin, a serotonin 2A receptor antagonist, alleviates ischemia-related biliary fibrosis following donation after cardiac death liver transplantation in rats
Liver Transpl.
2014
, vol. 
20
 (pg. 
1317
-
1326
)
[PubMed]
49
Chung
 
H.S.
Park
 
C.S.
Hong
 
S.H.
Lee
 
S.
Cho
 
M.L.
Her
 
Y.M.
Sa
 
G.J.
Lee
 
J.
Choi
 
J.H.
 
Effects of magnesium pretreatment on the levels of T helper cytokines and on the severity of reperfusion syndrome in patients undergoing living donor liver transplantation
Magnes. Res.
2013
, vol. 
26
 (pg. 
46
-
55
)
[PubMed]
50
Tang
 
Y.
Zhang
 
W.
Zhang
 
Y.
Wang
 
W.
Yao
 
F.
Yan
 
J.
Wan
 
C.
 
5′-Methylthioadenosine attenuates ischemia reperfusion injury after liver transplantation in rats
Inflammation
2014
, vol. 
37
 (pg. 
1366
-
1373
)
[PubMed]
51
D’Amico
 
F.
Vitale
 
A.
Piovan
 
D.
Bertacco
 
A.
Ramirez
 
M.R.
Chiara
 
F.A.
Bassi
 
D.
Bonsignore
 
P.
Gringeri
 
E.
Valmasoni
 
M.
, et al 
Use of N-acetylcysteine during liver procurement: a prospective randomized controlled study
Liver Transpl.
2013
, vol. 
19
 (pg. 
135
-
144
)
[PubMed]
52
Bezinover
 
D.
Ramamoorthy
 
S.
Postula
 
M.
Weller
 
G.
Mahmoud
 
S.
Mani
 
H.
Kadry
 
Z.
Uemura
 
T.
Mets
 
B.
Spiess
 
B.
, et al 
Effect of cold perfusion and perfluorocarbons on liver graft ischemia in a donation after cardiac death model
J. Surg. Res.
2014
, vol. 
188
 (pg. 
517
-
526
)
[PubMed]
53
Zhang
 
Y.
Ji
 
H.
Shen
 
X.
Cai
 
J.
Gao
 
F.
Koenig
 
K.M.
Batikian
 
C.M.
Busuttil
 
R.W.
Kupiec-Weglinski
 
J.W.
 
Targeting TIM-1 on CD4 T cells depresses macrophage activation and overcomes ischemia–reperfusion injury in mouse orthotopic liver transplantation
Am. J. Transplant.
2013
, vol. 
13
 (pg. 
56
-
66
)
[PubMed]
54
Gracia-Sancho
 
J.
Garcia-Caldero
 
H.
Hide
 
D.
Marrone
 
G.
Guixe-Muntet
 
S.
Peralta
 
C.
Garcia-Pagan
 
J.C.
Abraldes
 
J.G.
Bosch
 
J.
 
Simvastatin maintains function and viability of steatotic rat livers procured for transplantation
J. Hepatol.
2013
, vol. 
58
 (pg. 
1140
-
1146
)
[PubMed]
55
Liu
 
Z.Y.
Wang
 
W.
Jin
 
B.
Li
 
G.Z.
Du
 
G.
Zhang
 
Z.L.
Han
 
L.T.
Huang
 
G.Z.
Tang
 
Z.Y.
 
Protection against ischemia–reperfusion injury in aged liver donor by the induction of exogenous human telomerase reverse transcriptase gene
Transplant. Proc.
2014
, vol. 
46
 (pg. 
1567
-
1572
)
[PubMed]
56
Yoshida
 
O.
Kimura
 
S.
Jackson
 
E.K.
Robson
 
S.C.
Geller
 
D.A.
Murase
 
N.
Thomson
 
A.W.
 
CD39 expression by hepatic myeloid dendritic cells attenuates inflammation in liver transplant ischemia–reperfusion injury in mice
Hepatology
2013
, vol. 
58
 (pg. 
2163
-
2175
)
[PubMed]
57
Pommey
 
S.
Lu
 
B.
McRae
 
J.
Stagg
 
J.
Hill
 
P.
Salvaris
 
E.
Robson
 
S.C.
d’Apice
 
A.J.
Cowan
 
P.J.
Dwyer
 
K.M.
 
Liver grafts from CD39-overexpressing rodents are protected from ischemia reperfusion injury due to reduced numbers of resident CD4+ T cells
Hepatology
2013
, vol. 
57
 (pg. 
1597
-
1606
)
[PubMed]
58
Ke
 
B.
Shen
 
X.D.
Zhang
 
Y.
Ji
 
H.
Gao
 
F.
Yue
 
S.
Kamo
 
N.
Zhai
 
Y.
Yamamoto
 
M.
Busuttil
 
R.W.
Kupiec-Weglinski
 
J.W.
 
KEAP1–NRF2 complex in ischemia-induced hepatocellular damage of mouse liver transplants
J. Hepatol.
2013
, vol. 
59
 (pg. 
1200
-
1207
)
[PubMed]
59
Du
 
Z.
Wei
 
C.
Cheng
 
K.
Han
 
B.
Yan
 
J.
Zhang
 
M.
Peng
 
C.
Liu
 
Y.
 
Mesenchymal stem cell-conditioned medium reduces liver injury and enhances regeneration in reduced-size rat liver transplantation
J. Surg. Res.
2013
, vol. 
183
 (pg. 
907
-
915
)
[PubMed]
60
Bejaoui
 
M.
Zaouali
 
M.A.
Folch-Puy
 
E.
Pantazi
 
E.
Bardag-Gorce
 
F.
Carbonell
 
T.
Oliva
 
J.
Rimola
 
A.
Abdennebi
 
H.B.
Rosello-Catafau
 
J.
 
Bortezomib enhances fatty liver preservation in Institut George Lopez-1 solution through adenosine monophosphate activated protein kinase and Akt/mTOR pathways
J. Pharm. Pharmacol.
2014
, vol. 
66
 (pg. 
62
-
72
)
[PubMed]
61
Zaouali
 
M.A.
Bardag-Gorce
 
F.
Carbonell
 
T.
Oliva
 
J.
Pantazi
 
E.
Bejaoui
 
M.
Ben
 
A.H.
Rimola
 
A.
Rosello-Catafau
 
J.
 
Proteasome inhibitors protect the steatotic and non-steatotic liver graft against cold ischemia reperfusion injury
Exp. Mol. Pathol.
2013
, vol. 
94
 (pg. 
352
-
359
)
[PubMed]
62
Arthur
 
P.G.
Niu
 
X.W.
Huang
 
W.H.
Deboer
 
B.
Lai
 
C.T.
Rossi
 
E.
Joseph
 
J.
Jeffrey
 
G.P.
 
Desferrioxamine in warm reperfusion media decreases liver injury aggravated by cold storage
World J. Gastroenterol.
2013
, vol. 
19
 (pg. 
673
-
681
)
[PubMed]
63
Zaouali
 
M.A.
Boncompagni
 
E.
Reiter
 
R.J.
Bejaoui
 
M.
Freitas
 
I.
Pantazi
 
E.
Folch-Puy
 
E.
Abdennebi
 
H.B.
Garcia-Gil
 
F.A.
Rosello-Catafau
 
J.
 
AMPK involvement in endoplasmic reticulum stress and autophagy modulation after fatty liver graft preservation: a role for melatonin and trimetazidine cocktail
J. Pineal Res.
2013
, vol. 
55
 (pg. 
65
-
78
)
[PubMed]
64
Ishima
 
Y.
Shinagawa
 
T.
Yoneshige
 
S.
Kragh-Hansen
 
U.
Ohya
 
Y.
Inomata
 
Y.
Kai
 
T.
Otagiri
 
M.
Maruyama
 
T.
 
UW solution improved with high anti-apoptotic activity by S-nitrosated human serum albumin
Nitric Oxide
2013
, vol. 
30
 (pg. 
36
-
42
)
[PubMed]
65
Hara
 
Y.
Akamatsu
 
Y.
Maida
 
K.
Kashiwadate
 
T.
Kobayashi
 
Y.
Ohuchi
 
N.
Satomi
 
S.
 
A new liver graft preparation method for uncontrolled non-heart-beating donors, combining short oxygenated warm perfusion and prostaglandin E1
J. Surg. Res.
2013
, vol. 
184
 (pg. 
1134
-
1142
)
[PubMed]
66
Schlegel
 
A.
Kron
 
P.
Graf
 
R.
Dutkowski
 
P.
Clavien
 
P.A.
 
Warm vs. cold perfusion techniques to rescue rodent liver grafts
J. Hepatol.
2014
, vol. 
61
 (pg. 
1267
-
1275
)
[PubMed]
67
Schlegel
 
A.
Graf
 
R.
Clavien
 
P.A.
Dutkowski
 
P.
 
Hypothermic oxygenated perfusion (HOPE) protects from biliary injury in a rodent model of DCD liver transplantation
J. Hepatol.
2013
, vol. 
59
 (pg. 
984
-
991
)
[PubMed]
68
Schlegel
 
A.
Rougemont
 
O.
Graf
 
R.
Clavien
 
P.A.
Dutkowski
 
P.
 
Protective mechanisms of end-ischemic cold machine perfusion in DCD liver grafts
J. Hepatol.
2013
, vol. 
58
 (pg. 
278
-
286
)
[PubMed]
69
Ren
 
Z.
Cui
 
G.
Lu
 
H.
Chen
 
X.
Jiang
 
J.
Liu
 
H.
He
 
Y.
Ding
 
S.
Hu
 
Z.
Wang
 
W.
Zheng
 
S.
 
Liver ischemic preconditioning (IPC) improves intestinal microbiota following liver transplantation in rats through 16s rDNA-based analysis of microbial structure shift
PLoS ONE
2013
, vol. 
8
 pg. 
e75950
 
[PubMed]
70
Izamis
 
M.L.
Tolboom
 
H.
Uygun
 
B.
Berthiaume
 
F.
Yarmush
 
M.L.
Uygun
 
K.
 
Resuscitation of ischemic donor livers with normothermic machine perfusion: a metabolic flux analysis of treatment in rats
PLoS ONE
2013
, vol. 
8
 pg. 
e69758
 
[PubMed]
71
Shigeta
 
T.
Matsuno
 
N.
Obara
 
H.
Kanazawa
 
H.
Tanaka
 
H.
Fukuda
 
A.
Sakamoto
 
S.
Kasahara
 
M.
Mizunuma
 
H.
Enosawa
 
S.
 
Impact of rewarming preservation by continuous machine perfusion: improved post-transplant recovery in pigs
Transplant. Proc.
2013
, vol. 
45
 (pg. 
1684
-
1689
)
[PubMed]
72
Kim
 
W.H.
Lee
 
J.H.
Ko
 
J.S.
Min
 
J.J.
Gwak
 
M.S.
Kim
 
G.S.
Lee
 
S.K.
 
Effect of remote ischemic postconditioning on patients undergoing living donor liver transplantation
Liver Transpl.
2014
, vol. 
20
 (pg. 
1383
-
1392
)
[PubMed]
73
Nagai
 
K.
Yagi
 
S.
Afify
 
M.
Bleilevens
 
C.
Uemoto
 
S.
Tolba
 
R.H.
 
Impact of venous-systemic oxygen persufflation with nitric oxide gas on steatotic grafts after partial orthotopic liver transplantation in rats
Transplantation
2013
, vol. 
95
 (pg. 
78
-
84
)
[PubMed]
74
Yagi
 
S.
Nagai
 
K.
Kadaba
 
P.
Afify
 
M.
Teramukai
 
S.
Uemoto
 
S.
Tolba
 
R.H.
 
A novel organ preservation for small partial liver transplantations in rats: venous systemic oxygen persufflation with nitric oxide gas
Am. J. Transplant.
2013
, vol. 
13
 (pg. 
222
-
228
)
[PubMed]
75
Kageyama
 
S.
Yagi
 
S.
Tanaka
 
H.
Saito
 
S.
Nagai
 
K.
Hata
 
K.
Fujimoto
 
Y.
Ogura
 
Y.
Tolba
 
R.
Shinji
 
U.
 
Graft reconditioning with nitric oxide gas in rat liver transplantation from cardiac death donors
Transplantation
2014
, vol. 
97
 (pg. 
618
-
625
)
[PubMed]
76
Kudoh
 
K.
Uchinami
 
H.
Yoshioka
 
M.
Seki
 
E.
Yamamoto
 
Y.
 
Nrf2 activation protects the liver from ischemia/reperfusion injury in mice
Ann. Surg.
2014
, vol. 
260
 (pg. 
118
-
127
)
[PubMed]
77
Jiang
 
W.
Kong
 
L.
Ni
 
Q.
Lu
 
Y.
Ding
 
W.
Liu
 
G.
Pu
 
L.
Tang
 
W.
Kong
 
L.
 
miR-146a ameliorates liver ischemia/reperfusion injury by suppressing IRAK1 and TRAF6
PLoS ONE
2014
, vol. 
9
 pg. 
e101530
 
[PubMed]
78
Godwin
 
A.
Yang
 
W.L.
Sharma
 
A.
Khader
 
A.
Wang
 
Z.
Zhang
 
F.
Nicastro
 
J.
Coppa
 
G.F.
Wang
 
P.
 
Blocking cold-inducible RNA-binding protein (CIRP) protects liver from ischemia/reperfusion injury
Shock
2015
, vol. 
43
 (pg. 
24
-
30
)
[PubMed]
79
Yang
 
J.
Wang
 
X.
Song
 
S.
Liu
 
F.
Fu
 
Z.
Wang
 
Q.
 
Near-term anti-CD25 monoclonal antibody administration protects murine liver from ischemia–reperfusion injury due to reduced numbers of CD4+ T cells
PLoS ONE
2014
, vol. 
9
 pg. 
e106892
 
[PubMed]
80
Cámara-Lemarroy
 
C.R.
Guzmán-de la Garza
 
F.J.
Alarcón-Galván
 
G.
Cordero-Pérez
 
P.
Muñoz-Espinosa
 
L.
Torres-González
 
L.
Fernández-Garza
 
N.E.
 
Hepatic ischemia/reperfusion injury is diminished by atorvastatin in Wistar rats
Arch. Med. Res.
2014
, vol. 
45
 (pg. 
210
-
216
)
[PubMed]
81
Khandoga
 
A.
Mende
 
K.
Iskandarov
 
E.
Rosentreter
 
D.
Schelcher
 
C.
Reifart
 
J.
Jauch
 
K.W.
Thasler
 
W.E.
 
Augmenter of liver regeneration attenuates inflammatory response in the postischemic mouse liver in vivo
J. Surg. Res.
2014
, vol. 
192
 (pg. 
187
-
194
)
[PubMed]
82
Kitagawa
 
T.
Yokoyama
 
Y.
Kokuryo
 
T.
Nagino
 
M.
 
Protective effects of branched-chain amino acids on hepatic ischemia–reperfusion-induced liver injury in rats: a direct attenuation of Kupffer cell activation
Am. J. Physiol. Gastrointest. Liver Physiol.
2013
, vol. 
304
 (pg. 
G346
-
G355
)
[PubMed]
83
Liu
 
B.
Qian
 
J.
Wang
 
Q.
Wang
 
F.
Ma
 
Z.
Qiao
 
Y.
 
Butyrate protects rat liver against total hepatic ischemia reperfusion injury with bowel congestion
PLoS ONE
2014
, vol. 
9
 pg. 
e106184
 
[PubMed]
84
Saidi
 
R.F.
Rajeshkumar
 
B.
Shariftabrizi
 
A.
Dresser
 
K.
Walter
 
O.
 
Human C1 inhibitor attenuates liver ischemia–reperfusion injury and promotes liver regeneration
J. Surg. Res.
2014
, vol. 
187
 (pg. 
660
-
666
)
[PubMed]
85
Kim
 
H.J.
Joe
 
Y.
Kong
 
J.S.
Jeong
 
S.O.
Cho
 
G.J.
Ryter
 
S.W.
Chung
 
H.T.
 
Carbon monoxide protects against hepatic ischemia/reperfusion injury via ROS-dependent Akt signaling and inhibition of glycogen synthase kinase 3β
Oxid. Med. Cell Longev.
2013
, vol. 
2013
 pg. 
306421
 
[PubMed]
86
Yan
 
H.
Jihong
 
Y.
Feng
 
Z.
Xiaomei
 
X.
Xiaohan
 
Z.
Guangzhi
 
W.
Zhenhai
 
M.
Dongyan
 
G.
Xiaochi
 
M.
Qing
 
F.
, et al 
Sirtuin 1-mediated inhibition of p66shc expression alleviates liver ischemia/reperfusion injury
Crit. Care Med.
2014
, vol. 
42
 (pg. 
e373
-
e381
)
[PubMed]
87
Suo
 
L.
Kang
 
K.
Wang
 
X.
Cao
 
Y.
Zhao
 
H.
Sun
 
X.
Tong
 
L.
Zhang
 
F.
 
Carvacrol alleviates ischemia reperfusion injury by regulating the PI3K–Akt pathway in rats
PLoS ONE
2014
, vol. 
9
 pg. 
e104043
 
[PubMed]
88
Fang
 
H.
Liu
 
A.
Dahmen
 
U.
Dirsch
 
O.
 
Dual role of chloroquine in liver ischemia reperfusion injury: reduction of liver damage in early phase, but aggravation in late phase
Cell Death Dis.
2013
, vol. 
4
 pg. 
e694
 
[PubMed]
89
Ben-Ari
 
Z.
Issan
 
Y.
Katz
 
Y.
Sultan
 
M.
Safran
 
M.
Michal
 
L.S.
Nader
 
G.A.
Kornowski
 
R.
Grief
 
F.
Pappo
 
O.
Hochhauser
 
E.
 
Induction of heme oxygenase-1 protects mouse liver from apoptotic ischemia/reperfusion injury
Apoptosis
2013
, vol. 
18
 (pg. 
547
-
555
)
[PubMed]
90
Huang
 
J.
Yue
 
S.
Ke
 
B.
Zhu
 
J.
Shen
 
X.D.
Zhai
 
Y.
Yamamoto
 
M.
Busuttil
 
R.W.
Kupiec-Weglinski
 
J.W.
 
Nuclear factor erythroid 2-related factor 2 regulates Toll-like receptor 4 innate responses in mouse liver ischemia–reperfusion injury through Akt-forkhead box protein O1 signaling network
Transplantation
2014
, vol. 
98
 (pg. 
721
-
728
)
[PubMed]
91
Marshall
 
K.M.
He
 
S.
Zhong
 
Z.
Atkinson
 
C.
Tomlinson
 
S.
 
Dissecting the complement pathway in hepatic injury and regeneration with a novel protective strategy
J. Exp. Med.
2014
, vol. 
211
 (pg. 
1793
-
1805
)
[PubMed]
92
Sahin
 
T.
Begec
 
Z.
Toprak
 
H.I.
Polat
 
A.
Vardi
 
N.
Yucel
 
A.
Durmus
 
M.
Ersoy
 
M.O.
 
The effects of dexmedetomidine on liver ischemia–reperfusion injury in rats
J. Surg. Res.
2013
, vol. 
183
 (pg. 
385
-
390
)
[PubMed]
93
Teoh
 
N.C.
Ajamieh
 
H.
Wong
 
H.J.
Croft
 
K.
Mori
 
T.
Allison
 
A.C.
Farrell
 
G.C.
 
Microparticles mediate hepatic ischemia–reperfusion injury and are the targets of Diannexin (ASP8597)
PLoS ONE
2014
, vol. 
9
 pg. 
e104376
 
[PubMed]
94
Nogueira
 
M.A.
Coelho
 
A.M.
Sampietre
 
S.N.
Patzina
 
R.A.
Pinheiro da Silva
 
F.
D’Albuquerque
 
L.A.
Machado
 
M.C.
 
Beneficial effects of adenosine triphosphate-sensitive K+ channel opener on liver ischemia/reperfusion injury
World J. Gastroenterol.
2014
, vol. 
20
 (pg. 
15319
-
15326
)
[PubMed]
95
Tian
 
Y.S.
Rong
 
T.Z.
Hong
 
Y.L.
Min
 
L.
Jian
 
P.G.
 
Pharmacological postconditioning with diazoxide attenuates ischemia/reperfusion-induced injury in rat liver
Exp. Ther. Med.
2013
, vol. 
5
 (pg. 
1169
-
1173
)
[PubMed]
96
Tao
 
X.
Wan
 
X.
Xu
 
Y.
Xu
 
L.
Qi
 
Y.
Yin
 
L.
Han
 
X.
Lin
 
Y.
Peng
 
J.
 
Dioscin attenuates hepatic ischemia–reperfusion injury in rats through inhibition of oxidative–nitrative stress, inflammation and apoptosis
Transplantation
2014
, vol. 
98
 (pg. 
604
-
611
)
[PubMed]
97
Zimmerman
 
M.A.
Tak
 
E.
Ehrentraut
 
S.F.
Kaplan
 
M.
Giebler
 
A.
Weng
 
T.
Choi
 
D.S.
Blackburn
 
M.R.
Kam
 
I.
Eltzschig
 
H.K.
Grenz
 
A.
 
Equilibrative nucleoside transporter (ENT)-1-dependent elevation of extracellular adenosine protects the liver during ischemia and reperfusion
Hepatology
2013
, vol. 
58
 (pg. 
1766
-
1778
)
[PubMed]
98
Uchiyama
 
M.
Tojo
 
K.
Yazawa
 
T.
Ota
 
S.
Goto
 
T.
Kurahashi
 
K.
 
Edaravone prevents lung injury induced by hepatic ischemia–reperfusion
J. Surg. Res.
2015
, vol. 
194
 (pg. 
551
-
7
)
[PubMed]
99
Riehle
 
K.J.
Hoagland
 
V.
Benz
 
W.
Campbell
 
J.S.
Liggitt
 
D.H.
Langdale
 
L.A.
 
Hepatocellular heme oxygenase-1: a potential mechanism of erythropoietin-mediated protection after liver ischemia–reperfusion injury
Shock
2014
, vol. 
42
 (pg. 
424
-
431
)
[PubMed]
100
Shen
 
M.
Lu
 
J.
Dai
 
W.
Wang
 
F.
Xu
 
L.
Chen
 
K.
He
 
L.
Cheng
 
P.
Zhang
 
Y.
Wang
 
C.
, et al 
Ethyl pyruvate ameliorates hepatic ischemia–reperfusion injury by inhibiting intrinsic pathway of apoptosis and autophagy
Mediators Inflamm.
2013
, vol. 
2013
 pg. 
461536
 
[PubMed]
101
Gupta
 
N.A.
Kolachala
 
V.L.
Jiang
 
R.
Abramowsky
 
C.
Shenoi
 
A.
Kosters
 
A.
Pavuluri
 
H.
Anania
 
F.
Kirk
 
A.D.
 
Mitigation of autophagy ameliorates hepatocellular damage following ischemia–reperfusion injury in murine steatotic liver
Am. J. Physiol. Gastrointest. Liver Physiol.
2014
, vol. 
307
 (pg. 
G1088
-
G1099
)
[PubMed]
102
Rickenbacher
 
A.
Jang
 
J.H.
Limani
 
P.
Ungethum
 
U.
Lehmann
 
K.
Oberkofler
 
C.E.
Weber
 
A.
Graf
 
R.
Humar
 
B.
Clavien
 
P.A.
 
Fasting protects liver from ischemic injury through Sirt1-mediated downregulation of circulating HMGB1 in mice
J. Hepatol.
2014
, vol. 
61
 (pg. 
301
-
308
)
[PubMed]
103
Liu
 
A.
Fang
 
H.
Yang
 
Y.
Sun
 
J.
Fan
 
H.
Liu
 
S.
Dirsch
 
O.
Dahmen
 
U.
 
The fibrin-derived peptide bβ15–42 attenuates liver damage in a rat model of liver ischemia/reperfusion injury
Shock
2013
, vol. 
39
 (pg. 
397
-
403
)
[PubMed]
104
Zhang
 
R.
Zhang
 
L.
Manaenko
 
A.
Ye
 
Z.
Liu
 
W.
Sun
 
X.
 
Helium preconditioning protects mouse liver against ischemia and reperfusion injury through the PI3K/Akt pathway
J. Hepatol.
2014
, vol. 
61
 (pg. 
1048
-
1055
)
[PubMed]
105
Huang
 
X.
Gao
 
Y.
Qin
 
J.
Lu
 
S.
 
The role of miR-34a in the hepatoprotective effect of hydrogen sulfide on ischemia/reperfusion injury in young and old rats
PLoS ONE
2014
, vol. 
9
 pg. 
e113305
 
[PubMed]
106
Shimada
 
S.
Fukai
 
M.
Wakayama
 
K.
Ishikawa
 
T.
Kobayashi
 
N.
Kimura
 
T.
Yamashita
 
K.
Kamiyama
 
T.
Shimamura
 
T.
Taketomi
 
A.
Todo
 
S.
 
Hydrogen sulfide augments survival signals in warm ischemia and reperfusion of the mouse liver
Surg. Today
2014
 
doi:10.1007/s00595-014-1064-4
107
Hanaoka
 
J.
Shimada
 
M.
Utsunomiya
 
T.
Morine
 
Y.
Imura
 
S.
Ikemoto
 
T.
Mori
 
H.
Sugimoto
 
K.
Saito
 
Y.
Yamada
 
S.
Asanoma
 
M.
 
Beneficial effects of enteral nutrition containing with hydrolyzed whey peptide on warm ischemia/reperfusion injury in the rat liver
Hepatol. Res.
2014
, vol. 
44
 (pg. 
114
-
121
)
[PubMed]
108
Nii
 
A.
Utsunomiya
 
T.
Shimada
 
M.
Ikegami
 
T.
Ishibashi
 
H.
Imura
 
S.
Morine
 
Y.
Ikemoto
 
T.
Sasaki
 
H.
Kawashima
 
A.
 
A hydrolyzed whey peptide-based diet ameliorates hepatic ischemia–reperfusion injury in the rat nonalcoholic fatty liver
Surg. Today
2014
, vol. 
44
 (pg. 
2354
-
2360
)
[PubMed]
109
Pan
 
S.
Liu
 
L.
Pan
 
H.
Ma
 
Y.
Wang
 
D.
Kang
 
K.
Wang
 
J.
Sun
 
B.
Sun
 
X.
Jiang
 
H.
 
Protective effects of hydroxytyrosol on liver ischemia/reperfusion injury in mice
Mol. Nutr. Food Res.
2013
, vol. 
57
 (pg. 
1218
-
1227
)
[PubMed]
110
Losada
 
D.M.
Chies
 
A.B.
Feres
 
O.
Chaib
 
E.
D’Albuquerque
 
L.A.
Castro-e-Silva
 
 
Effects of hyperbaric oxygen therapy as hepatic preconditioning in rats submitted to hepatic ischemia/reperfusion injury
Acta Cir. Bras.
2014
, vol. 
29
 (pg. 
61
-
66
)
[PubMed]
111
Hartmann
 
P.
Fet
 
N.
Garab
 
D.
Szabo
 
A.
Kaszaki
 
J.
Srinivasan
 
P.K.
Tolba
 
R.H.
Boros
 
M.
 
l-α-glycerylphosphorylcholine reduces the microcirculatory dysfunction and nicotinamide adenine dinucleotide phosphate-oxidase type 4 induction after partial hepatic ischemia in rats
J. Surg. Res.
2014
, vol. 
189
 (pg. 
32
-
40
)
[PubMed]
112
Ibrahim
 
M.A.
Abdel-Gaber
 
S.A.
Amin
 
E.F.
Ibrahim
 
S.A.
Mohammed
 
R.K.
Abdelrahman
 
A.M.
 
Molecular mechanisms contributing to the protective effect of levosimendan in liver ischemia–reperfusion injury
Eur. J. Pharmacol.
2014
, vol. 
741
 (pg. 
64
-
73
)
[PubMed]
113
Onody
 
P.
Stangl
 
R.
Fulop
 
A.
Rosero
 
O.
Garbaisz
 
D.
Turoczi
 
Z.
Lotz
 
G.
Rakonczay
 
Z.
Balla
 
Z.
Hegedus
 
V.
, et al 
Levosimendan: a cardiovascular drug to prevent liver ischemia–reperfusion injury?
PLoS ONE
2013
, vol. 
8
 pg. 
e73758
 
[PubMed]
114
Mahmoud
 
M.F.
Gamal
 
S.
El-Fayoumi
 
H.M.
 
Limonin attenuates hepatocellular injury following liver ischemia and reperfusion in rats via Toll-like receptor dependent pathway
Eur. J. Pharmacol.
2014
, vol. 
740
 (pg. 
676
-
682
)
[PubMed]
115
Liu
 
A.
Fang
 
H.
Dahmen
 
U.
Dirsch
 
O.
 
Chronic lithium treatment protects against liver ischemia/reperfusion injury in rats
Liver Transpl.
2013
, vol. 
19
 (pg. 
762
-
772
)
[PubMed]
116
Koh
 
E.J.
Yoon
 
S.J.
Lee
 
S.M.
 
Losartan protects liver against ischaemia/reperfusion injury through PPAR-γ activation and receptor for advanced glycation end-products down-regulation
Br. J. Pharmacol.
2013
, vol. 
169
 (pg. 
1404
-
1416
)
[PubMed]
117
Rao
 
J.
Qin
 
J.
Qian
 
X.
Lu
 
L.
Wang
 
P.
Wu
 
Z.
Zhai
 
Y.
Zhang
 
F.
Li
 
G.
Wang
 
X.
 
Lipopolysaccharide preconditioning protects hepatocytes from ischemia/reperfusion injury (IRI) through inhibiting ATF4–CHOP pathway in mice
PLoS ONE
2013
, vol. 
8
 pg. 
e65568
 
[PubMed]
118
Takhtfooladi
 
M.A.
Takhtfooladi
 
H.A.
Khansari
 
M.
 
The effects of low-intensity laser therapy on hepatic ischemia–reperfusion injury in a rat model
Lasers Med. Sci.
2014
, vol. 
29
 (pg. 
1887
-
1893
)
[PubMed]
119
Kireev
 
R.
Bitoun
 
S.
Cuesta
 
S.
Tejerina
 
A.
Ibarrola
 
C.
Moreno
 
E.
Vara
 
E.
Tresguerres
 
J.A.
 
Melatonin treatment protects liver of Zucker rats after ischemia/reperfusion by diminishing oxidative stress and apoptosis
Eur. J. Pharmacol.
2013
, vol. 
701
 (pg. 
185
-
193
)
[PubMed]
120
Li
 
L.
Li
 
G.
Yu
 
C.
Shen
 
Z.
Xu
 
C.
Feng
 
Z.
Zhang
 
X.
Li
 
Y.
 
A role of microRNA-370 in hepatic ischaemia–reperfusion injury by targeting transforming growth factor-β receptor II
Liver Int.
2013
, vol. 
35
 (pg. 
1124
-
1132
)
121
Li
 
Y.
Li
 
T.
Qi
 
H.
Yuan
 
F.
 
Minocycline protects against hepatic ischemia/reperfusion injury in a rat model
Biomed. Rep.
2015
, vol. 
3
 (pg. 
19
-
24
)
[PubMed]
122
Sun
 
Y.
Pu
 
L.Y.
Lu
 
L.
Wang
 
X.H.
Zhang
 
F.
Rao
 
J.H.
 
N-acetylcysteine attenuates reactive-oxygen-species-mediated endoplasmic reticulum stress during liver ischemia–reperfusion injury
World J. Gastroenterol.
2014
, vol. 
20
 (pg. 
15289
-
15298
)
[PubMed]
123
Katsumi
 
H.
Fukui
 
K.
Sato
 
K.
Maruyama
 
S.
Yamashita
 
S.
Mizumoto
 
E.
Kusamori
 
K.
Oyama
 
M.
Sano
 
M.
Sakane
 
T.
Yamamoto
 
A.
 
Pharmacokinetics and preventive effects of platinum nanoparticles as reactive oxygen species scavengers on hepatic ischemia/reperfusion injury in mice
Metallomics
2014
, vol. 
6
 (pg. 
1050
-
1056
)
[PubMed]
124
Zhao
 
G.
Ma
 
H.
Shen
 
X.
Xu
 
G.F.
Zhu
 
Y.L.
Chen
 
B.
Tie
 
R.
Qu
 
P.
Lv
 
Y.
Zhang
 
H.
Yu
 
J.
 
Role of glycogen synthase kinase 3β in protective effect of propofol against hepatic ischemia–reperfusion injury
J. Surg. Res.
2013
, vol. 
185
 (pg. 
388
-
398
)
[PubMed]
125
Mende
 
K.
Reifart
 
J.
Rosentreter
 
D.
Manukyan
 
D.
Mayr
 
D.
Krombach
 
F.
Rentsch
 
M.
Khandoga
 
A.
 
Targeting platelet migration in the postischemic liver by blocking protease-activated receptor 4
Transplantation
2014
, vol. 
97
 (pg. 
154
-
160
)
[PubMed]
126
Zhu
 
J.
Lu
 
T.
Yue
 
S.
Shen
 
X.
Gao
 
F.
Busuttil
 
R.W.
Kupiec-Weglinski
 
J.W.
Xia
 
Q.
Zhai
 
Y.
 
Rapamycin protection of livers from ischemia and reperfusion injury is dependent on both autophagy induction and mammalian target of rapamycin complex 2–Akt activation
Transplantation
2015
, vol. 
99
 (pg. 
48
-
55
)
[PubMed]
127
Suyavaran
 
A.
Ramamurthy
 
C.
Mareeswaran
 
R.
Subastri
 
A.
Lokeswara
 
R.P.
Thirunavukkarasu
 
C.
 
TNF-α suppression by glutathione preconditioning attenuates hepatic ischemia reperfusion injury in young and aged rats
Inflamm. Res.
2015
, vol. 
64
 (pg. 
71
-
81
)
[PubMed]
128
Kuroda
 
S.
Tashiro
 
H.
Kimura
 
Y.
Hirata
 
K.
Tsutada
 
M.
Mikuriya
 
Y.
Kobayashi
 
T.
Amano
 
H.
Tanaka
 
Y.
Ohdan
 
H.
 
Rho-kinase inhibitor targeting liver prevents ischemic reperfusion injury in steatotic liver without major systemic adverse in rat
Liver Transpl.
2015
, vol. 
21
 (pg. 
123
-
131
)
[PubMed]
129
Sanches
 
S.C.
Ramalho
 
L.N.
Mendes-Braz
 
M.
Terra
 
V.A.
Cecchini
 
R.
Augusto
 
M.J.
Ramalho
 
F.S.
 
Riboflavin (vitamin B-2) reduces hepatocellular injury following liver ischaemia and reperfusion in mice
Food Chem. Toxicol.
2014
, vol. 
67
 (pg. 
65
-
71
)
[PubMed]
130
Ramalho
 
L.N.
Pasta
 
A.A.
Terra
 
V.A.
Augusto
 
M.J.
Sanches
 
S.C.
Souza-Neto
 
F.P.
Cecchini
 
R.
Gulin
 
F.
Ramalho
 
F.S.
 
Rosmarinic acid attenuates hepatic ischemia and reperfusion injury in rats
Food Chem. Toxicol.
2014
, vol. 
74C
 (pg. 
270
-
278
)
131
Balzan
 
S.M.
Gava
 
V.G.
Rieger
 
A.
Pra
 
D.
Trombini
 
L.
Zenkner
 
F.F.
Horta
 
J.A.
Azambuja
 
G.
Schopf
 
L.
de Souza
 
P.L.
 
Ischemic versus pharmacologic hepatic preconditioning
J. Surg. Res.
2014
, vol. 
191
 (pg. 
134
-
139
)
[PubMed]
132
Zhou
 
S.P.
Jiang
 
P.
Liu
 
L.
Liu
 
H.
 
Protective effect of sevoflurane on hepatic ischaemia/reperfusion injury in the rat: a dose–response study
Eur. J. Anaesthesiol.
2013
, vol. 
30
 (pg. 
612
-
617
)
133
Savvanis
 
S.
Nastos
 
C.
Tasoulis
 
M.K.
Papoutsidakis
 
N.
Demonakou
 
M.
Karmaniolou
 
I.
Arkadopoulos
 
N.
Smyrniotis
 
V.
Theodoraki
 
K.
 
Sildenafil attenuates hepatocellular injury after liver ischemia reperfusion in rats: a preliminary study
Oxid. Med. Cell Longev.
2014
, vol. 
2014
 pg. 
161942
 
[PubMed]
134
Sakai
 
S.
Tajima
 
H.
Miyashita
 
T.
Nakanuma
 
S.
Makino
 
I.
Hayashi
 
H.
Nakagawara
 
H.
Kitagawa
 
H.
Fushida
 
S.
Fujimura
 
T.
, et al 
Sivelestat sodium hydrate inhibits neutrophil migration to the vessel wall and suppresses hepatic ischemia–reperfusion injury
Dig. Dis. Sci.
2014
, vol. 
59
 (pg. 
787
-
794
)
[PubMed]
135
Tanemura
 
A.
Kuriyama
 
N.
Azumi
 
Y.
Ohsawa
 
I.
Kishiwada
 
M.
Mizuno
 
S.
Usui
 
M.
Sakurai
 
H.
Tabata
 
M.
Isaji
 
S.
 
Thrombomodulin administration attenuates ischemia–reperfusion injury of the remnant liver after 70% hepatectomy in rats: simulated model of small-for-size graft in living donor liver transplantation
Transplant. Proc.
2014
, vol. 
46
 (pg. 
1107
-
1111
)
[PubMed]
136
Ji
 
H.
Zhang
 
Y.
Liu
 
Y.
Shen
 
X.D.
Gao
 
F.
Nguyen
 
T.T.
Busuttil
 
R.W.
Waschek
 
J.A.
Kupiec-Weglinski
 
J.W.
 
Vasoactive intestinal peptide attenuates liver ischemia/reperfusion injury in mice via the cyclic adenosine monophosphate–protein kinase A pathway
Liver Transpl.
2013
, vol. 
19
 (pg. 
945
-
956
)
[PubMed]
137
Park
 
J.
Kang
 
J.W.
Lee
 
S.M.
 
Activation of the cholinergic anti-inflammatory pathway by nicotine attenuates hepatic ischemia/reperfusion injury via heme oxygenase-1 induction
Eur. J. Pharmacol.
2013
, vol. 
707
 (pg. 
61
-
70
)
[PubMed]
138
Li
 
F.
Chen
 
Z.
Pan
 
Q.
Fu
 
S.
Lin
 
F.
Ren
 
H.
Han
 
H.
Billiar
 
T.R.
Sun
 
F.
Li
 
Q.
 
The protective effect of PNU-282987, a selective α7 nicotinic acetylcholine receptor agonist, on the hepatic ischemia–reperfusion injury is associated with the inhibition of high-mobility group box 1 protein expression and nuclear factor κB activation in mice
Shock
2013
, vol. 
39
 (pg. 
197
-
203
)
[PubMed]
139
Raptis
 
D.A.
Limani
 
P.
Jang
 
J.H.
Ungethum
 
U.
Tschuor
 
C.
Graf
 
R.
Humar
 
B.
Clavien
 
P.A.
 
GPR120 on Kupffer cells mediates hepatoprotective effects of ω3-fatty acids
J. Hepatol.
2014
, vol. 
60
 (pg. 
625
-
632
)
[PubMed]
140
Kim
 
K.
Jung
 
N.
Lee
 
K.
Choi
 
J.
Kim
 
S.
Jun
 
J.
Kim
 
E.
Kim
 
D.
 
Dietary ω−3 polyunsaturated fatty acids attenuate hepatic ischemia/reperfusion injury in rats by modulating Toll-like receptor recruitment into lipid rafts
Clin. Nutr.
2013
, vol. 
32
 (pg. 
855
-
862
)
[PubMed]
141
Saito
 
Y.
Shimada
 
M.
Utsunomiya
 
T.
Ikemoto
 
T.
Yamada
 
S.
Morine
 
Y.
Imura
 
S.
Mori
 
H.
Sugimoto
 
K.
Iwahashi
 
S.
Asanoma
 
M.
 
The protective effect of adipose-derived stem cells against liver injury by trophic molecules
J. Surg. Res.
2013
, vol. 
180
 (pg. 
162
-
168
)
[PubMed]
142
Rao
 
J.
Yue
 
S.
Fu
 
Y.
Zhu
 
J.
Wang
 
X.
Busuttil
 
R.W.
Kupiec-Weglinski
 
J.W.
Lu
 
L.
Zhai
 
Y.
 
ATF6 mediates a pro-inflammatory synergy between ER stress and TLR activation in the pathogenesis of liver ischemia–reperfusion injury
Am. J. Transplant.
2014
, vol. 
14
 (pg. 
1552
-
1561
)
[PubMed]
143
Jin
 
G.
Qiu
 
G.
Wu
 
D.
Hu
 
Y.
Qiao
 
P.
Fan
 
C.
Gao
 
F.
 
Allogeneic bone marrow-derived mesenchymal stem cells attenuate hepatic ischemia–reperfusion injury by suppressing oxidative stress and inhibiting apoptosis in rats
Int. J. Mol. Med.
2013
, vol. 
31
 (pg. 
1395
-
1401
)
[PubMed]
144
Cai
 
C.
Shi
 
X.
Korff
 
S.
Zhang
 
J.
Loughran
 
P.A.
Ruan
 
X.
Zhang
 
Y.
Liu
 
L.
Billiar
 
T.R.
 
CD14 contributes to warm hepatic ischemia–reperfusion injury in mice
Shock
2013
, vol. 
40
 (pg. 
115
-
121
)
[PubMed]
145
Feng
 
M.
Wang
 
Q.
Wang
 
H.
Wang
 
M.
Guan
 
W.
Lu
 
L.
 
Adoptive transfer of hepatic stellate cells ameliorates liver ischemia reperfusion injury through enriching regulatory T cells
Int. Immunopharmacol.
2014
, vol. 
19
 (pg. 
267
-
274
)
[PubMed]
146
Saidi
 
R.F.
Rajeshkumar
 
B.
Shariftabrizi
 
A.
Bogdanov
 
A.A.
Zheng
 
S.
Dresser
 
K.
Walter
 
O.
 
Human adipose-derived mesenchymal stem cells attenuate liver ischemia–reperfusion injury and promote liver regeneration
Surgery
2014
, vol. 
156
 (pg. 
1225
-
1231
)
[PubMed]
147
Wang
 
P.X.
Zhang
 
R.
Huang
 
L.
Zhu
 
L.H.
Jiang
 
D.S.
Chen
 
H.Z.
Zhang
 
Y.
Tian
 
S.
Zhang
 
X.F.
Zhang
 
X.D.
, et al 
Interferon regulatory factor 9 is a key mediator of hepatic ischemia/reperfusion injury
J. Hepatol.
2015
, vol. 
62
 (pg. 
111
-
120
)
[PubMed]
148
Lin
 
H.C.
Liu
 
S.Y.
Lai
 
H.S.
Lai
 
I.R.
 
Isolated mitochondria infusion mitigates ischemia–reperfusion injury of the liver in rats
Shock
2013
, vol. 
39
 (pg. 
304
-
310
)
[PubMed]
149
Chen
 
Z.
Jia
 
S.
Li
 
D.
Cai
 
J.
Tu
 
J.
Geng
 
B.
Guan
 
Y.
Cui
 
Q.
Yang
 
J.
 
Silencing of long noncoding RNA AK139328 attenuates ischemia/reperfusion injury in mouse livers
PLoS ONE
2013
, vol. 
8
 pg. 
e80817
 
[PubMed]
150
Fu
 
J.
Zhang
 
H.
Zhuang
 
Y.
Liu
 
H.
Shi
 
Q.
Li
 
D.
Ju
 
X.
 
The role of N-acetyltransferase 8 in mesenchymal stem cell-based therapy for liver ischemia/reperfusion injury in rats
PLoS ONE
2014
, vol. 
9
 pg. 
e103355
 
[PubMed]
151
Li
 
J.
Ke
 
W.
Zhou
 
Q.
Wu
 
Y.
Luo
 
H.
Zhou
 
H.
Yang
 
B.
Guo
 
Y.
Zheng
 
Q.
Zhang
 
Y.
 
Tumour necrosis factor-α promotes liver ischaemia–reperfusion injury through the PGC-1α/Mfn2 pathway
J. Cell. Mol. Med.
2014
, vol. 
18
 (pg. 
1863
-
1873
)
[PubMed]
152
Yue
 
S.
Rao
 
J.
Zhu
 
J.
Busuttil
 
R.W.
Kupiec-Weglinski
 
J.W.
Lu
 
L.
Wang
 
X.
Zhai
 
Y.
 
Myeloid PTEN deficiency protects livers from ischemia reperfusion injury by facilitating M2 macrophage differentiation
J. Immunol.
2014
, vol. 
192
 (pg. 
5343
-
5353
)
[PubMed]
153
Schlegel
 
M.
Granja
 
T.
Kaiser
 
S.
Korner
 
A.
Henes
 
J.
Konig
 
K.
Straub
 
A.
Rosenberger
 
P.
Mirakaj
 
V.
 
Inhibition of neogenin dampens hepatic ischemia–reperfusion injury
Crit. Care Med.
2014
, vol. 
42
 (pg. 
e610
-
e619
)
[PubMed]
154
Inoue
 
Y.
Shirasuna
 
K.
Kimura
 
H.
Usui
 
F.
Kawashima
 
A.
Karasawa
 
T.
Tago
 
K.
Dezaki
 
K.
Nishimura
 
S.
Sagara
 
J.
, et al 
NLRP3 regulates neutrophil functions and contributes to hepatic ischemia–reperfusion injury independently of inflammasomes
J. Immunol.
2014
, vol. 
192
 (pg. 
4342
-
4351
)
[PubMed]
155
Ji
 
H.
Liu
 
Y.
Zhang
 
Y.
Shen
 
X.D.
Gao
 
F.
Busuttil
 
R.W.
Kuchroo
 
V.K.
Kupiec-Weglinski
 
J.W.
 
T-cell immunoglobulin and mucin domain 4 (TIM-4) signaling in innate immune-mediated liver ischemia–reperfusion injury
Hepatology
2014
, vol. 
60
 (pg. 
2052
-
2064
)
[PubMed]
156
Nace
 
G.W.
Huang
 
H.
Klune
 
J.R.
Eid
 
R.E.
Rosborough
 
B.R.
Korff
 
S.
Li
 
S.
Shapiro
 
R.A.
Stolz
 
D.B.
Sodhi
 
C.P.
, et al 
Cellular-specific role of Toll-like receptor 4 in hepatic ischemia–reperfusion injury in mice
Hepatology
2013
, vol. 
58
 (pg. 
374
-
387
)
[PubMed]
157
Meimei
 
H.
Dejin
 
M.
Erzhen
 
C.
Minmin
 
S.
Songyao
 
J.
Jianfang
 
L.
Hao
 
C.
 
Inhibiting the Toll-like receptor 4 Toll/interleukin-1 receptor domain protects against hepatic warm ischemia and reperfusion injury in mice
Crit. Care Med.
2014
, vol. 
42
 (pg. 
e123
-
e131
)
[PubMed]
158
Liu
 
A.
Fang
 
H.
Wei
 
W.
Dirsch
 
O.
Dahmen
 
U.
 
Ischemic preconditioning protects against liver ischemia/reperfusion injury via heme oxygenase-1-mediated autophagy
Crit. Care Med.
2014
, vol. 
42
 (pg. 
e762
-
e771
)
[PubMed]
159
Pantazi
 
E.
Zaouali
 
M.A.
Bejaoui
 
M.
Serafin
 
A.
Folch-Puy
 
E.
Petegnief
 
V.
De Vera
 
N.
Ben Abdennebi
 
H.
Rimola
 
A.
Rosello-Catafau
 
J.
 
Silent information regulator 1 protects the liver against ischemia–reperfusion injury: implications in steatotic liver ischemic preconditioning
Transpl. Int.
2014
, vol. 
27
 (pg. 
493
-
503
)
[PubMed]
160
Fu
 
H.
Xu
 
H.
Chen
 
H.
Li
 
Y.
Li
 
W.
Zhu
 
Q.
Zhang
 
Q.
Yuan
 
H.
Liu
 
F.
Wang
 
Q.
Miao
 
M.
Shi
 
X.
 
Inhibition of glycogen synthase kinase 3 ameliorates liver ischemia/reperfusion injury via an energy-dependent mitochondrial mechanism
J. Hepatol.
2014
, vol. 
61
 (pg. 
816
-
824
)
[PubMed]
161
Czigany
 
Z.
Turoczi
 
Z.
Kleiner
 
D.
Lotz
 
G.
Homeyer
 
A.
Harsanyi
 
L.
Szijarto
 
A.
 
Neural elements behind the hepatoprotection of remote preconditioning
J. Surg. Res.
2015
, vol. 
193
 (pg. 
642
-
651
)
[PubMed]
162
Kageyama
 
S.
Hata
 
K.
Tanaka
 
H.
Hirao
 
H.
Kubota
 
T.
Okamura
 
Y.
Iwaisako
 
K.
Takada
 
Y.
Uemoto
 
S.
 
Intestinal Ischemic preconditioning ameliorates hepatic ischemia reperfusion injury in rats: role of heme oxygenase-1 in the second-window of protection
Liver Transpl.
2015
, vol. 
21
 (pg. 
112
-
122
)
[PubMed]
163
Wang
 
Y.
Shen
 
J.
Xiong
 
X.
Xu
 
Y.
Zhang
 
H.
Huang
 
C.
Tian
 
Y.
Jiao
 
C.
Wang
 
X.
Li
 
X.
 
Remote ischemic preconditioning protects against liver ischemia–reperfusion injury via heme oxygenase-1-induced autophagy
PLoS ONE
2014
, vol. 
9
 pg. 
e98834
 
[PubMed]
164
Garab
 
D.
Fet
 
N.
Szabo
 
A.
Tolba
 
R.H.
Boros
 
M.
Hartmann
 
P.
 
Remote ischemic preconditioning differentially affects NADPH oxidase isoforms during hepatic ischemia–reperfusion
Life Sci.
2014
, vol. 
105
 (pg. 
14
-
21
)
[PubMed]