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Clinical Science (2015) 129, 345–362 doi: 10.1042/CS20150223
Molecular pathways in protecting the liver from
ischaemia/reperfusion injury: a 2015 update
Jordi Gracia-Sancho∗,Aran
´
ı Casillas-Ram´
ırez†‡ and Carmen Peralta†
∗Barcelona Hepatic Hemodynamic Laboratory, Institut d’Investigacions Biom`
ediques August Pi i Sunyer (IDIBAPS), Centro de Investigaci´
on Biom´
edica
en Red en Enfermedades Hep´
aticas y Digestivas (CIBEREHD), Barcelona, Spain
†Institut d’Investigacions Biom`
ediques August Pi i Sunyer (IDIBAPS), Centro de Investigaci´
on Biom´
edica en Red en Enfermedades Hep´
aticas y
Digestivas (CIBEREHD), Barcelona, Spain
‡Hospital Regional de Alta Especialidad de Ciudad Victoria “Bicentenario 2010”, Cd. Victoria, Mexico
Abstract
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.
Key words: cold storage, hepatocytes, liver microcirculation, liver sinusoidal endothelial cells, LSEC, warm ischaemia.
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 im-
plicated in I/R has led to several controversies, and even discrep-
ancies, in our understanding of this pathology. Carefully reading
the literature, we hypothesize that disagreements in I/R mechan-
isms, 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 mod-
els of cold and warm ischaemia. In addition, some of the most
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, Kr ¨
uppel-like factor 2; LSEC, liver sinusoidal endothelial cells; MAPK, mitogen-activated protein kinase; MMP, matrix
metalloproteinase; NMP, nor mothermic machine perfusion; Nrf2, nuclear factor-erythroid 2-related factor 2; PAMP, pathogen-associated molecular pattern; PH, par tial hepatectomy;
RBP4, retinol-binding protein 4; TLR, Toll-like receptor.
Correspondence: Dr Jordi Gracia-Sancho (email jgracia@clinic.ub.es).
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 occur-
ring 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 im-
paired 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
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The Authors Journal compilation C
2015 Biochemical Society 345
Clinical Science www.clinsci.org
J. Gracia-Sancho, A. Casillas-Ram´
ırez and C. Peralta
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-as-
sociated molecular patterns; eNOS, endothelial nitric oxide synthase; ET, endothelin; IL, interleukin; IRF-1, interferon
regulatory factor-1; KC, Kupffer cells; KLF2, Kr¨
uppel-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.
fact, experimental studies of liver preservation for transplant-
ation 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 viab-
ility, and vice versa.
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 re-
cruitment 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 mechan-
isms involved in cold ischaemia injury where sinusoidal cells
play a key role. The lack of biomechanical stimuli occurring dur-
ing cold preservation for transplantation markedly deteriorates
the LSEC protective phenotype by down-regulating the expres-
sion of the transcription factor KLF2 (Kr¨
uppel-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 antioxid-
ant 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 neigh-
bouring 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 trans-
plantation 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
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Underlying mechanisms of hepatic I/R injury
and improved graft survival; nevertheless, better characteriza-
tion of this process, focusing on each hepatic cell type, is still
necessary. In this regard, a recent communication by Biel and col-
leagues 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 el-
evated in serum from patients after liver transplantation, posit-
ively correlating with aminotransferase levels [10]. As experi-
mental studies have shown that miRNAs are feasible targets for
therapeutic interventions designed to minimize injury caused by
ischaemic insults, further studies targeting HDmiRs might elu-
cidate 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 re-
sponses. 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 produc-
tion of inflammatory mediators, activation of apoptotic pathways
and activation of MAPK (mitogen-activated protein kinase) path-
ways [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 func-
tion. 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 pat-
ent 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 trans-
ition of cold to warm ischaemia, maintaining the liver graft at a
single temperature from retrieval until implantation. The under-
lying principle of NMP is the combination of continuous circu-
lation 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 normother-
mia, in association with an oxygenated blood-based perfusion
solution, in comparison with cold storage procedures [17–19].
Furthermore, in situ normothermic regional perfusion of dona-
tion after cardiac death is gaining in popularity and has resulted
in a number of successful liver transplantations [20–24].
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 sig-
nalling). In addition, in the specific scenario of machine perfu-
sion, a significant part of work aimed to characterize the pos-
sible 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 de-
scribed that combines machine perfusion at subnormothermic
conditions with a new haemoglobin-based oxygen carrier solu-
tion, triggering regenerative and cell protective responses result-
ing in improved allograft function [25].
WARM ISCHAEMIA
Mechanisms of injury
Warm I/R injury is responsible for significant organ dysfunction
and failure after liver resection and haemorrhagic shock. Histor-
ically, it has been considered that hepatocytes are more sensitive
to warm I/R, whereas LSEC are more sensitive to cold I/R. How-
ever, limitation of injury to a particular cell type is rare under
pathophysiological conditions; indeed evidencesuggest profound
sinusoidal deregulation during warm I/R injury [26]. Similarly
to liver cold I/R injury, Kupffer cells play a key role in warm
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J. Gracia-Sancho, A. Casillas-Ram´
ırez and C. Peralta
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
Drug Species Experimental model
Cold ischaemia
time Effect
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 [49] Human 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 strategy Species Experimental model
Cold ischaemia
time Effect
Ad-hTERT [55] (human telomerase transcriptase) Rat Liver transplantation (aged grafts) 2 h ↓Hepatic injury and apoptosis; ↑telomerase activity
CD39−/−in myeloid dendritic cells [56] Mouse Liver transplantation 24 h ↓Hepatic injury; ↑pro-inflammator y cytokines
CD39-transgenic [57] (CD39-overexpression) Mouse Liver transplantation 18 h ↓Hepatic injury, IL-6, CD4+T-cells and invariant NKT cells
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Underlying mechanisms of hepatic I/R injury
Table 1 Continued
(b) Gene and cell therapy strategies
Target gene/cell therapy strategy Species Experimental model
Cold ischaemia
time Effect
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 additive Species Experimental model
Cold ischaemia
time Effect
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 PGE1in UW solution [65] (short
oxygenated warm perfusion and prostaglandin E1)Rat
Ex vivo liver perfusion (uncontrolled NHBD
grafts) 6 h ↓Hepatic injury, necrosis and apoptosis
(d) Surgical and machine perfusion-based strategies
Strategy Species Experimental model/clinical setting
Cold ischaemia
time Effect
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 [71] Pig 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
[25] Pig 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
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J. Gracia-Sancho, A. Casillas-Ram´
ırez and C. Peralta
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. Interest-
ingly, recent data indicate that cardiolipin (diphosphatidylgly-
cerol), a phospholipid required for efficient mitochondrial func-
tion, 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 mitochon-
drial 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 funda-
mental biological processes. Protein acetylation by histone acet-
yltransferases enhances gene expression via relaxation of chro-
matin 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 acet-
ylation 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 undergo-
ing warm I/R injury, it was demonstrated that MMP-9 activ-
ity disrupts vascular integrity through a PECAM-1 (platelet en-
dothelial cell adhesion molecule-1)-dependent mechanism, and
interferes with liver regeneration [29]. Similar findings were ob-
served 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 hepatec-
tomy) 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 ob-
served 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 di-
minish 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 in-
jury 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, pro-
moting 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 adipo-
cytokines 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.
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, in-
terventional studies can be performed, and tools for targeted ma-
nipulation of gene expression provide insight into the function of
mediators in hepatic I/R injury. Comparison of the results of an-
imal 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 an-
imals are of limited applicability to human beings due to their
different size and anatomy of the liver and their faster metabol-
ism. 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 con-
sidering 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 de-
pend 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
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Underlying mechanisms of hepatic I/R 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, Kr¨
uppel-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.
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 effect-
iveness 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 use-
ful to make a clear distinction between the mechanisms for each
surgical situation to design therapies that demonstrate its effect-
iveness 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 neutro-
phils 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 vasopro-
tective pathways are rapidly deregulated in LSEC submitted to
warm I/R, leading to endothelial dysfunction development and
massive inflammation [39]. Undoubtedly, future studies will cla-
rify 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 import-
ant 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.
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J. Gracia-Sancho, A. Casillas-Ram´
ırez and C. Peralta
Table 2 Therapeutic approaches against warm I/R injur y
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
Drug Species Experimental model
War m
ischaemia Effect
15-deoxy-12,14-prostaglandin J2[76] Mouse 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-146a)
Mouse 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 [79] Mouse 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 [81] Mouse 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 Par tial 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
352 C
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Underlying mechanisms of hepatic I/R injury
Table 2 Continued
(a) Pharmacological strategies
Drug Species Experimental model
War m
ischaemia Effect
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 liver s) 20 min ↓Hepatic injury and autophagy; peserves mitochondrial integrity
Fasting [102] Mouse 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 [104] Mouse Partial ischaemia 90 min ↓Hepatic injur y; ↑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 [107,108] Rat 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 [110] Rat 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 [115] Rat Total and partial ischaemia 60–90 min ↓Hepatic injur y; ↓inflammation and HMGB1
Losartan [116] (angiotensin receptor antagonist) Mouse Partial ischaemia 60 min ↓Hepatic injury, apoptosis and inflammation; ↑PPARγ
Low-dose LPS [117] Mouse Partial ischaemia 90 min ↓Hepatic injury, apoptosis, inflammation, and ATF4/CHOP pathway
Low-intensity laser therapy [118] Rat 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 [120] Mouse Partial ischaemia 75 min ↓Hepatic injury; ↓inflammatory response
Minocycline [121] (antibiotic) Rat Partial ischaemia 2, 6 and 24 h ↓Hepatic injur y, oxidative stress and inflammatory cytokines;
activation of Wnt/β-catenin signalling pathway
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The Authors Journal compilation C
2015 Biochemical Society 353
J. Gracia-Sancho, A. Casillas-Ram´
ırez and C. Peralta
Table 2 Continued
(a) Pharmacological strategies
Drug Species Experimental model
War m
ischaemia Effect
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 [123] Mouse Total ischaemia 15 min ↓Hepatic injury
Propofol73 [124] (anaesthetic) Rat Partial ischaemia 30, 60, 90 min ↓Hepatic injur y, 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 injur y; ↑autophagy, Akt
Reduced glutathione [127] (antioxidant) Rat Partial ischaemia (young and aged
rats)
90 min ↓Hepatic injury, oxidative stress, TNFαand 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 [128] Rat Total ischaemia (steatotic livers) 45 min ↓Hepatic injury, portal perfusion pressure; ↑survival
Riboflavin [129] (vitamin B2) Mice 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 [136] Mouse Partial ischaemia 90 min ↓Hepatic injury, apoptosis and inflammation; ↑cAMP/PKA
signalling
α7 Nicotinic acetylcholine receptor
activator/agonist [137,138]
Mouse Partial ischaemia 60 min ↓Hepatic injury, oxidative stress, inflammation, TNFαand HMGB1;
↑HO-1, PI3K/Akt, Nrf2
ω−3 Fatty acid formulation [139,140] Mouse Partial ischaemia 60 min ↓Hepatic injury and inflammation; ↑GPR120
354 C
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Underlying mechanisms of hepatic I/R injury
Table 2 Continued
(b) Gene and cell therapy strategies
Target gene/cell therapy strategy Species Experimental model Warm ischaemia Effect
Adipose-derived stem cells [141] Mouse Partial ischaemia 15, 20 min ↓Hepatic injury; ↑liver regeneration
ATF6 siRNA [142] (activating transcription factor 6) Mouse Partial ischaemia 90 min ↓Hepatic injur y, ER stress, inflammation; ↑macrophage TLR4
response, Akt activation
Bone-marrow-derived mesenchymal stem cells [143] Rat Partial ischaemia 60 min ↓Hepatic injur y, oxidative stress and apoptosis
CD14−/−[144] Mouse Partial ischaemia 60 min ↓Hepatic injur y, inflammation and apoptosis
ENT1−/−[97] (equilibrative nucleoside transporter 1) Mouse Partial ischaemia 45 min ↓Hepatic injury; ↑adenosine regulation of Adora2b receptor
Hepatic stellate cells [145] Mouse Partial ischaemia Not reported ↓Hepatic injur y; ↑Tre g s
Human adipose-derived mesenchymal stem cells [146] Mouse Partial ischaemia with or without partial
hepatectomy
60 min ↓Hepatic injury; ↑liver regeneration and survival
Interferon regulatory factor 9−/−[147] Mouse Partial ischaemia Not reported ↓Hepatic injury, inflammation and apoptosis; ↑SIRT1
Isolated viable mitochondria infusion [148] Rat Partial ischaemia 45 min ↓Hepatic injury and apoptosis
Long non-coding RNA AK139328 siRNA [149] Rat Partial ischaemia 60 min ↓Hepatic injury, apoptosis and inflammation; ↑Akt, GSK3β
activation, eNOS
Mesenchymal stem cells [150] Rat Total ischaemia 30 min ↓Hepatic injury and apoptosis
Mfn2 overexpression [151] (mitochondrial function
modulator)
Rat Partial ischaemia 90 min ↓Hepatic injur y 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 injur y and inflammation; ↑IL-10, macrophage
differentiation
Neogenin−/−[153] Mouse Partial ischaemia 30 min ↓Hepatic injur y and inflammation
NLRP3−/−[154] (NOD-like receptor family, pyrin
domain-containing 3)
Mouse Partial ischaemia 60 min ↓Hepatic injur y, inflammation, oxidative stress, apoptosis and
neutrophil infiltration
TIM-4−/−[155] (T-cell immunoglobulin and mucin 4) Mouse Partial ischaemia 90 min ↓Hepatic injur y 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 [157] Mouse Partial ischaemia 90 min ↓Hepatic injury, oxidative stress, inflammation and TLR4
(c) Surgical strategies
Strategy Species Experimental model/clinical setting
Warm ischaemia
time Effect
IPC [158] Rat Partial ischaemia (young and aged rats) 60 min ↓Hepatic injur y; ↑autophagy, HO-1
IPC [86,159] Rat
Partial ischaemia (steatotic and
non-steatotic livers) 45–60 min ↓Hepatic injury and p66shc ;↑SOD and SIRT1
IPC [131] Swine Total ischaemia 40 min ↓Hepatic injury
IPC or GSK3 inhibitor [160] Rat Partial ischaemia (young and aged rats) 40 min ↓Hepatic injury and oxidative stress; ↑ATP
RPC [161] Rat Partial ischaemia 60 min ↓Hepatic injur y; ↑microcirculation and blood pressure
RPC [162] Rat Total ischaemia 30 min ↓Hepatic injur y; ↑survival and HO-1
RPC [163] Rat Partial ischaemia 45 min ↓Hepatic injur y; ↑HO-1/p38 MAPK-dependent and autophagy
RPC [164] Rat Partial ischaemia 60 min ↓Hepatic injur y, inflammation and NADPH oxidase isoform 2
C
The Authors Journal compilation C
2015 Biochemical Society 355
J. Gracia-Sancho, A. Casillas-Ram´
ırez and C. Peralta
ACKNOWLEDGEMENTS
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.
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Published on the Internet 21 May 2015, doi: 10.1042/CS20150223
362 C
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