Autophagy and Liver Ischemia-Reperfusion Injury

Cursio, Raffaele; Colosetti, Pascal; Gugenheim, Jean

doi:https://doi.org/10.1155/2015/417590

BioMed Research International

On this page

Abstract Introduction Conclusion References Copyright Related Articles

Special Issue

The Role of Autophagy in Liver Diseases: Mechanisms and Potential Therapeutic Targets

View this Special Issue

Review Article | Open Access

Volume 2015 | Article ID 417590 | https://doi.org/10.1155/2015/417590

Autophagy and Liver Ischemia-Reperfusion Injury

Raffaele Cursio,^1,2Pascal Colosetti,²and Jean Gugenheim¹

Academic Editor: Han-Ming Shen

Received13 Jun 2014

Revised21 Aug 2014

Accepted07 Sept 2014

Published15 Mar 2015

Abstract

Liver ischemia-reperfusion (I-R) injury occurs during liver resection, liver transplantation, and hemorrhagic shock. The main mode of liver cell death after warm and/or cold liver I-R is necrosis, but other modes of cell death, as apoptosis and autophagy, are also involved. Autophagy is an intracellular self-digesting pathway responsible for removal of long-lived proteins, damaged organelles, and malformed proteins during biosynthesis by lysosomes. Autophagy is found in normal and diseased liver. Although depending on the type of ischemia, warm and/or cold, the dynamic process of liver I-R results mainly in adenosine triphosphate depletion and in production of reactive oxygen species (ROS), leads to both, a local ischemic insult and an acute inflammatory-mediated reperfusion injury, and results finally in cell death. This process can induce liver dysfunction and can increase patient morbidity and mortality after liver surgery and hemorrhagic shock. Whether autophagy protects from or promotes liver injury following warm and/or cold I-R remains to be elucidated. The present review aims to summarize the current knowledge in liver I-R injury focusing on both the beneficial and the detrimental effects of liver autophagy following warm and/or cold liver I-R.

1. Introduction

Partial or complete interruption of the liver blood flow and, consequently, interruption of its oxygen supply, followed by reperfusion and reestablishment of blood flow and oxygen supply, characterizes the liver ischemia-reperfusion (I-R) process. The cellular injuries caused by the ischemic period are aggravated by reperfusion [1–4]. Not only liver transplantation or resection but also liver injury following blunt or penetrating abdominal trauma [5] and hemorrhagic shock [6] may cause low liver blood flow resulting in insufficient perfusion. Finally after reperfusion liver I-R injury occurs. Liver I-R injury following hemorrhagic shock remains a major cause of morbidity and mortality after trauma [6]. Liver I-R rapidly leads to an acute inflammatory response, causing significant hepatocellular damage and organ dysfunction. The severity of injury ranges from moderately raised levels of serum aminotransferases to posthepatectomy insufficiency after liver resection or to primary nonfunction or initial poor graft function after liver transplantation [7–13]. Under extreme circumstances, multiple organ failure and death may occur. More precisely, in liver transplantation, up to 10% of early transplant failures are caused by I-R injury with a higher incidence of both acute and chronic graft rejection increasing the need for retransplantation [9–13]. Liver I-R may also be responsible for ischemic-type biliary lesions (ITBls) [14–16] and late allograft failure [17, 18]. The use of marginal liver grafts from non-heart-beating donors, older and/or steatotic organs, and of organs that have been subjected to prolonged periods of warm ischemia and cold storage, has increased in the last years due to organ shortage [19]. These grafts are more vulnerable to warm/cold I-R injury [19] underlining the need of therapeutic strategies to reduce liver I-R injury in order to improve graft viability [20].

Necrosis represents the main mode of liver cell death following warm/cold I-R [21–23], but other modes of cell death, namely, apoptosis [2, 24, 25] and autophagy [26–48], also play an important role.

Mammalian autophagy is an intracellular self-digesting pathway responsible for the removal of long-lived proteins, damaged organelles, and malformed proteins during biosynthesis by lysosomes [49]. Autophagy is divided into three main types according to the different pathway by which cargo is delivered to the lysosome or vacuole: chaperone-mediated autophagy (CMA), microautophagy, and macroautophagy [50]. The last type can be divided into six principal steps: initiation, nucleation, elongation, closure, maturation, and degradation or extrusion [49]. Through these steps cytoplasmic materials, such as protein aggregates and organelles, are sequestered by the phagophore, a preautophagosomal membrane structure, which thereafter expands and encloses its cargo to form a double-membrane vesicle, the autophagosome [51]. By its fusion with a lysosome, it forms an autolysosome, in which the enclosed cargo is degraded by acid hydrolases into biologically active monomers such as amino acids that are subsequently reused to maintain cellular metabolic turnover and homeostasis [51].

Autophagy is involved in normal and diseased liver [52–55]. Studies on autophagy in liver tissue following warm/cold I-R remain controversial. Some show defective and/or decreased autophagy [27–30, 32, 34–37, 39–41, 45, 47]; in others hepatocellular autophagy is increased [26, 31, 33, 38, 42–44, 46, 48]. Whether autophagy protects from or promotes liver injury following warm and/or cold I-R remains to be elucidated.

2. Pathomechanisms of Warm and/or Cold Liver I-R Injury

Warm ischemia of the liver is due to oxygen deficiency caused by vascular occlusion of the liver during liver resection or hemorrhagic shock [2, 10]. Cold ischemia is observed during liver transplantation in which the graft is subjected to warm and cold ischemia followed by a warm reperfusion phase; the warm/cold ischemia sequence is due to vascular occlusion of the liver graft during its procurement from the donor and to graft storage in cold preservation solutions before liver transplantation [2, 10]. Graft implantation into the recipient represents the warm reperfusion phase; all these phases lead to I-R injury of the liver [2, 10]. Pathomechanisms associated with warm I-R seem to differ from those after cold I-R in liver transplantation [57]. Unlike warm liver I-R, which results in primary damage to the hepatocytes, cold I-R is mainly characterized by injury to the sinusoidal lining cells [58–60].

The introduction of oxygenated blood during reperfusion aggravates the ischemic insult, which itself is mainly characterized by cellular adenosine triphosphate (ATP) depletion and results in perturbation of the cellular energy-dependent metabolic and transport processes [1, 61]. Although the graft metabolism is reduced during hypothermia, with a prolonged time period in which the anoxic cells can retain essential metabolic functions, hypothermia may induce liver injury by dysfunction of the Na/K ATPase membrane pump [61, 62]. The resulting intracellular influx and accumulation of sodium and chloride lead to a perturbation of calcium homeostasis and to cell swelling [61, 62]. The inflammatory response to liver I-R involves neutrophils, cytokines, chemokines, complement, monocytes, and macrophages [63–67]. The reperfusion process consists of two phases: in the initial phase, activated resident macrophages of the liver, the Kupffer cells, induce oxidative stress mainly by reactive oxygen species (ROS) generation and, in the later phase, 6–24 hours following reperfusion, recruited neutrophils release inflammatory mediators which can cause direct tissue damage [1]. Kupffer cells play a central role in the pathophysiological mechanisms of liver I-R. Activated Kupffer cells release both ROS and cytokines, including tumor necrosis factor alpha (TNF), Interleukin-1 (IL-1), and Interleukin-6 (IL-6), leading to granulocytes accumulation in the sinusoidal space and causing microcirculatory disturbances [68]. Accumulation of activated neutrophils through release of oxidants and proteases leads to hepatocyte damage. ROS stimulate endothelial cells to secrete platelet activating factor (PAF) [69]. Monocytes and Kupffer cells-derived ROS activate redox-sensitive transcription factors AP-1 and nuclear factor kappa-B (NF-B) in endothelial cells and hepatocytes [65]. Complement activation products activate Kupffer cells during the initial phase of liver injury and contribute to tissue inflammation as a membrane-attacking complex that stimulates the production of proinflammatory cytokines and chemotactic agents, which occur immediately after reperfusion [63]. Complement can also regulate the adaptative immunity [70, 71]. In fact, the inflammation occurring during liver reperfusion is predominantly an innate-immune-dominated response, which might induce I-R injury in both parenchymal and nonparenchymal cells, in situ and in liver transplants [66, 67, 72, 73]. However, the cold preservation injury of the graft causes a likewise strong adaptative immune response characterized by an early and massive T-cell influx into the ischemic liver graft [73–75]. The conventional T lymphocytes, CD4+ cells, accumulate in the liver within 1 hour after reperfusion preceding any neutrophil accumulation [76]. CD4+ cells are activated by various Kupffer cell-derived products and lead to hepatocytes and sinusoidal endothelial cells damage [76] and finally liver cells necrosis [22, 23, 77]. Apoptosis seems to be a relevant death mechanism during warm/cold liver I-R injury too [2, 24, 25] even if the studies are controversial on this issue [21, 24, 25]. Recently, the role of liver autophagy following warm and/or cold liver I-R has been highlighted [78].

3. Autophagy and Warm and/or Cold Liver I-R Injury

Beside necrosis [21–23] there are other modes of cell death, as apoptosis [2, 24, 25] and autophagy, that may occur simultaneously and or sequentially [26–48, 78] following warm and/or cold liver I-R. While some studies have shown a defective autophagy in hepatocytes following anoxia/reoxygenation and in liver tissue following I-R [27–30, 32, 34–37, 39–41, 45, 47], in others an increase of autophagy has been observed [26, 31, 33, 38, 42–44, 46, 48] (Table 1) with different effects on warm and/or cold liver I-R injury (Figure 1).

3.1. Protective Role of Autophagy against Warm and/or Cold Liver I-R Injury

3.1.1. In Vitro and In Vivo Animal Studies

The mammalian orthologue of yeast autophagy-related gene 6 (Atg6), Beclin 1, has an important role in autophagosome formation as a component of multiprotein class III phosphatidyl inositol-3 kinase (PI3K) complex [79]. Beclin 1 is important for localization of autophagic proteins to preautophagosomal membrane structure during the nucleation step of autophagy [80]. Reduced Beclin 1 levels have been observed in hepatocytes during anoxia/reoxygenation in mice [37] and following 45 min warm liver I-R in rats [27]. Increased expression of the autophagic protein Beclin 1 by nutrient deprivation, by its pharmacologic induction, and by its adenoviral overexpression during anoxia/reoxygenation in mouse hepatocytes in vitro [37] and in rat livers following I-R injury in vivo [32] protects hepatocytes from cell death and reduces liver I-R injury [27, 32, 37].

Impaired liver autophagy seems to be mediated by calcium overload and consequent Calpain 1 and Calpain 2 activation which mediates the proteolytic clivage of the autophagic protein Beclin 1 and/or of Atg7 in anoxic hepatocytes [27] and in livers following total warm I-R [27, 45]. Defective autophagy may culminate in onset of mitochondrial permeability transition (MPT) and hepatocyte death after reoxygenation [27]. MPT results in either, necrosis by uncoupling of oxidative phosphorylation and apoptosis by releasing proapoptotic factors that are normally sequestered in the mitochondrial intermembrane space [77, 81]. MPT acts also as a molecular signal initiating the autophagic degradation of mitochondria, the mitophagy [82]. Impaired mitophagy following liver I-R fails to remove dysfunctional mitochondria, the mitochondria loaded with ROS undergo MPT, which in turn leads to uncoupling of oxidative phosphorylation, energetic failure, ATP depletion, and ultimately cell death [27, 82]. During liver I-R, Kupffer cells, neutrophils, and platelets are activated. Their activation results in a generation and release of ROS and in a cascade of inflammatory events including release of proinflammatory cytokines such as TNFα, IL-2, IL-6, IL-1, and high mobility group box 1 (HMGB1) protein [83]. HMGB1 is a DNA binding protein, which, when secreted actively by nonparenchymal liver cells (Kupffer cells and endothelial cells) and by neutrophils or when passively released by necrotic liver cells [84, 85], may induce an inflammatory signaling cascade [86]. HMGB1 acts as an alarmin, an alarm protein signal that initiates the inflammatory response resulting from liver I-R [87]. In normal rat liver, HMGB1 is mainly present in the nuclei of hepatocytes [87]. HMGB1 was released into the effluent collected from the infrahepatic vena cava during prolonged cold saline preservation of isolated rat liver grafts [88]. After cold liver graft preservation for 6 hours and transplantation in rats, serum levels of HMGB1 were increased in the early reperfusion phase [89]. Following 60 warm partial liver I-R in mice [86] and following 90 min warm partial liver I-R in rats [90], HMGB1 translocated from the nucleus to the cytoplasm of hepatocytes and was released into the blood circulation within 1 hour after reperfusion. During warm liver I-R, tissue levels of HMGB1 increase with its innate immune activation requiring toll-like receptor 4- (TLR4-) dependent signaling already 1 hour following reperfusion and continue to increase for up to 24 h later [87]. In human liver transplantation, the peak of HMGB1 serum levels was observed 10 min after reperfusion; thereafter, it started to decrease progressively within 1-2 hours [91]. In vitro, nontoxic concentrations of Cisplatin, a platinating chemotherapeutic, can sequester HMGB1 inside the nucleus of hypoxic rat hepatocytes, can increase Beclin 1 expression, can modulate liver I-R-induced MAPK activation, and can induce autophagy [32]. These abilities of Cisplatin had beneficial effects on warm liver I-R injury and were also observed in vivo in mice [32]. In fact, in vivo administration of nontoxic concentrations of Cisplatin prevented HMGB1 release induced by 60 min partial warm liver I-R and reduced subsequent liver injury in mice [32]. Liver I-R alone increased Beclin 1 and Atg8/microtubule-associated protein 1 light chain 3 (LC3) expression; LC3 is also involved in the formation and expansion of the autophagosome; however, after Cisplatin administration, this increase was more pronounced and associated to mitophagy and finally proved to be protective against liver I-R injury [32].

The processing and degradation of LC3, from the unconjugated form microtubule-associated protein 1 light chain 1 (LC3-I) to the conjugated form microtubule-associated protein 1 light chain 2 (LC3-II), which remains associated to the autophagolysosome, indicate an increase in autophagy [49–51].

In rats, 60 min partial warm liver ischemia resulted in increased liver LC3-II. LC3-II is associated with the autophagosomal membrane allowing the closure of the autophagic vacuole and increases Atg5 expression which, when associated in a protein complex with Atg12 and Atg16, leads to autophagosome formation and finally to increased autophagy during reperfusion [42]. This liver I-R-induced LC3-II and Atg5 expression was more pronounced after chronic Lithium pretreatment of rats [42]. In fact, Lithium can induce autophagy by inhibiting inositol monophosphatase (IMPase) and leads to free inositol depletion which in turn may decrease myo-inositol-1,4,5-triphosphate (IP3) levels [92]. Induction of liver autophagy by chronic Lithium treatment before induction of 60 min partial warm ischemia was associated with reduced I-R liver injury, lower hepatic inflammatory cytokines levels, less liver neutrophil infiltration, and lower liver HMGB1 expression and serum HMGB1 levels [42].

It has been shown that the serine/threonine kinase Akt, also known as protein kinase B (PKB), plays a key role in cell survival and proliferation and may protect against liver I-R injury [93–96]. Hepatocytic anoxia/reoxygenation and 90 min partial warm liver I-R in mice resulted in a moderate but significant increase of hepatocellular levels of autophagy [38]. Hydrogen sulphide (H₂S) pretreatment of mice exerted a protective effect in both hepatocytic anoxia/reoxygenation and 90 min partial warm liver I-R injuries through Akt1 activation [38]. However, H₂S pretreatment suppressed the moderate but significant increase of liver autophagy levels occurring during hepatocyte reoxygenation and during warm liver reperfusion. In both experimental conditions, pretreatment with the autophagic inducer Rapamycin, which induces autophagy by binding with cochaperone immunophilin FKBP1 to specifically inhibit the mammalian target of Rapamycin (mTOR) complex 1, can reverse the autophagic inhibition of H₂S and enhances its hepatoprotective effects [38].

Reducing ROS-induced hepatocellular necrosis seems to be another protective role of autophagy in 90 min partial warm liver ischemia injury in rats [43]. Following 90 min partial warm liver ischemia without reperfusion, both increased levels of LC3-II and increased number of autophagosomes were observed [43]. These increases were associated with generation of mitochondrial ROS and liver injury [43]. When autophagy was inhibited by the autophagy inhibitor Chloroquine, the increase of mitochondrial oxidative stress, of ROS production, and of mitochondrial damage was even more pronounced [43]. The consequent accumulation of damaged mitochondria, which are normally sequestered and degraded through autophagy, leads to an enhanced ROS production with a subsequent acceleration of ischemia-induced liver injury and an increase of hepatocellular necrosis [97].

Decreased autophagy is a physiological consequence of aging [98]. In vitro hepatocyte I-R and in vivo warm liver I-R injury associated with autophagy seems to be age-dependent [28, 34]. In vitro old mice hepatocytes subjected to 2 hours of hypoxia followed by 12 hours of reoxygenation and in vivo 20 min total warm liver ischemia followed by 40 min reperfusion showed an increase in Calpain 2 activity, which hydrolyzed Atg4B and led to impaired autophagosome formation, impaired autophagic flux and mitophagy, and promoted the onset of the MPT and subsequent cell death [34]. The activation of peroxisome proliferator-activated receptor gamma (PPARγ), which belongs to the hormone nuclear receptor superfamily, is downregulated during liver ischemia aggravating liver injury [99]. PPARγ activation was lost in old mice after 30 min partial warm liver ischemia [28]. This suppression of PPARγ activation was accompanied by a reduced liver autophagy, which was more important in correlation with the duration of ischemia. Pretreatment of mice with the autophagy inducer Rosiglitazone, activated PPRAγ and increased liver autophagy after warm ischemia [28].

Steatotic livers have an increased risk of postoperative complications after liver resection [100] and liver transplantation [101]. They are particularly susceptible to mitochondrial alterations after storage in cold preservation solutions for transplantation [102, 103]. Steatosis may provide a substrate that promotes not only oxidative stress but indirectly also oxidant injury by decreasing the autophagic function [104, 105]. An impaired autophagy was observed during cold I-R of steatotic rat livers [40, 41]. Pretreatment with some autophagic stimulators, as well as Trimetazidine and Simvastatine, increased liver autophagy and improved I-R injuries of steatotic rat livers submitted to cold I-R [40, 41].

The use of hypothermic reconditioning (HR), a surgical technique consisting of temporary hypothermic oxygenation of the grafts by using an oxygenated machine perfusion or gaseous oxygen persufflation, may improve graft function and viability [106, 107]. HR of steatotic livers by insufflation of gaseous oxygen via the cava vein during the last 90 minutes of cold preservation of the graft has limited mitochondrial dysfunction and restored basal rates of hepatocellular autophagy in rats [30]. The beneficial effects of HR on liver grafts have also been shown in transplantation of nonsteatotic pig livers, where hepatocellular autophagy was preserved, mitigating the activation of innate immunity and leading to an improved survival of recipients [36].

3.1.2. In Vitro and In Vivo Human Studies

In primary isolated human hepatocytes, autophagy is a cell survival mechanism during oxidative stress [39]. Isolated primary human hepatocytes, which were exposed ex vivo to hypoxia and hypoxia-reoxygenation, showed an increase of autophagy within the mitochondria [39]. Inhibition of autophagy by 3-methyladenine (3-MA) in these stressed hepatocytes resulted in the lowering of MPT and onset of cell death by apoptosis [39]. During warm and cold liver I-R, ROS are responsible for lipid peroxidation, protease activation, cytokine release, adhesion molecule expression, microcirculatory failure, and finally apoptosis and necrosis [63]. However, ROS are also critical mediators of autophagy [108] and, during hypoxia-reoxygenation of primary human hepatocytes, inhibition of their production by N-acetylcysteine (NAC), Rotenone, and Diphenyliodonium suppressed autophagy and led to reduced levels of apoptosis and necrosis [39]. Thus, ROS seem to be key mediators of autophagy during oxidative stress and, depending on either the absolute level of intracellular ROS, the type of ROS subspecies generated, or the duration of ROS generation, they may be critical factors in determining cell death by apoptosis or necrosis [22, 23, 39].

Ischemic preconditioning (IP) of the liver is a surgical procedure consisting of a short period of liver ischemia (10 min) followed by reperfusion (10 min). Then the prolonged period of ischemia by clamping the hepatic artery and the portal vein on the hepatic pedicule (Pringle maneuver) is better supported by the liver [109]. After promising results in animal models, IP was efficiently used in clinical studies [110, 111]. However, its benefit to protect the liver from I-R injury in liver resection and transplantation in humans remains controversial [112–115]. A recent meta-analysis of IP for liver resection in patients with and without chronic liver diseases failed to find a significant benefit of IP in liver resection [115]. Also, in liver transplantation, there were no clear benefits of IP [112, 113]. Hepatosteatosis and vascular injury induced by chemotherapy can reduce tolerance of the liver to reperfusion injury and increase the risk of subsequent liver failure [116, 117]. In steatotic human livers formerly treated by chemotherapy, the use of IP before prolonged ischemia required by liver resection resulted in limited hepatocyte necrosis and was associated with an activation of liver autophagy [29]. The beneficial effects of IP on liver I-R injury seem to be a consequence of autophagy onset leading to preserved ATP levels and avoiding hepatocellular necrosis by delaying proapoptotic effects [29]. In liver transplantation IP of steatotic grafts (preconditioning in the donor before graft removal) induced autophagy, limited necrosis in human recipients, and decreased the incidence of rejection episodes [35]. In the ischemic preconditioned steatotic graft, a cellular increase of Beclin 1 and LC3 was observed, compared with non-IP steatotic liver grafts [35]. In addition, there was an inverse correlation between the number of LC3-positive cells and the necrotic index in IP steatotic liver grafts [35]. IP decreased the incidence of both acute and chronic liver rejection in recipients of steatotic grafts compared to recipients of non-IP steatotic grafts [35].

Overall, these studies showed that restoration or enhancement of autophagy may improve liver I-R injury by providing cells with the energy derived from lysosomal degradation of cellular materials [118].

3.2. Detrimental Role of Autophagy in Warm and/or Cold Liver I-R Injury

3.2.1. In Vitro and In Vivo Animal Studies

Several studies have shown increased levels of autophagy in hepatocytes following anoxia/reoxygenation and in livers following warm or cold/warm I-R [26, 31, 33, 38, 42–44, 46, 48]. These increased levels of autophagy appeared, either detrimental [26], probably protective [31], or both protective in the early phase of reperfusion and detrimental in the late phase of liver reperfusion [44]. Furthermore, when pharmacologically modulated, inhibited [33, 46, 48] or stimulated [38, 42, 43] autophagy improved warm and/or cold liver I-R injury in both cases.

Increased autophagy was observed following partial 120 min warm liver ischemia in rats 6 hours after reperfusion [31]. The hepatocytes of the ischemic liver lobes, 6 hours after reperfusion, had dense bodies and various autophagosomes as well as oval and rounded mitochondria [31]. The number of hepatocytes with punctate LC3 staining in the cytoplasm was markedly increased in ischemic compared to nonischemic liver lobes [31]. During orthotopic LT in rat, autophagosomes/autolysosomes were observed in graft hepatocytes in both cold preservation and reperfusion phases [26]. Induction of autophagy was more pronounced in graft hepatocytes after 30 to 60 min of warm reperfusion than in hepatocytes after cold preservation [26]. Abundant autophagosomes/autolysosomes were associated with dying hepatocytes within 2 hours of warm reperfusion [26]. Warm reperfusion phase may facilitate autophagosome formation in hepatocytes under ATP exhaustion as a stress response [26]. About 15 minutes after the start of warm reperfusion, small masses of hepatocytes with abundant autophagosomes/autolysosomes frequently dissociated from the hepatic cords and were extruded into the sinusoidal lumen [33]. Occlusion of the sinusoidal stream contributed to a massive necrosis of hepatocytes within 2 hours and led to liver dysfunction [33]. The hepatocytes containing numerous vacuolar/lysosomal structures often underwent degeneration and were phagocytosed by Kupffer cells late in the reperfusion phase [26]. The inhibition of autophagosome formation and maturation by adding the autophagic inhibitor Wortmannin and LY294002, a specific inhibitor of PI3K/Akt kinase pathway, to the cold preservation solution attenuated liver dysfunction and recipient mortality rates [33].

The beneficial effects of Rapamycin by reversing the autophagic inhibition of H₂S during hepatocytic anoxia/reoxygenation and 90 min partial warm liver I-R in mice [38] are in contrast with the detrimental effects of Rapamycin on reperfused livers following partial warm 60 min liver ischemia in mice shown in a recent study [48]. In fact the increased levels of autophagy induced by warm reperfusion were even higher after Rapamycin pretreatment and this excessive activation of autophagy aggravated liver I-R injury [48]. Furthermore, in the same study, Rapamycin reversed the beneficial effects of Melatonin administration, a lipophilic indole secreted by pineal and nonpineal cells, which seems to protect against liver I-R injury by inhibiting oxidative stress and by improving both mitochondrial respiration and ATP synthesis after cold storage of the liver [119, 120]. In this study, Melatonin downregulated autophagy via activation of mTOR signaling and resulted in improvement of liver I-R injury [48].

In contrast, in moderate and advanced steatotic cold-stored and warm-reperfused livers in rats, in which autophagy was impaired [40], Melatonin associated with Trimetazidine, induced liver autophagy, and improved liver injury [41]. When adding Simvastatine, a statin possessing vasoprotective properties, to the cold-storage solution, the bioavailability of the vasoprotector NO was maintained and led to autophagy induction [40]. Simvastatin treatment prevented hepatic endothelial dysfunction not only in steatotic [40] but also in nonsteatotic [121] livers and resulted in improvement of liver injury.

An increased level of autophagy was observed also in rat liver following 60 and 90 min partial warm liver I-R [44]. LC3-II protein was increased at 6 hours after liver reperfusion; this increase was more pronounced when rats were pretreated with the antimalaria drug Chloroquine [44]. Chloroquine seems to have a dual role in warm liver I-R; in fact, it improved liver injury in the early phase of reperfusion by reducing inflammatory cytokines, as well as IL-6, IL-1, and TNFα; it diminished HMGB1 release, and it modified I-R-induced MAP kinase activation [44]. In the late phase of reperfusion, however, Chloroquine inhibited autophagy and induced apoptosis aggravating liver I-R injuries [44]. By contrast, in another study, levels of autophagy were decreased earlier in hepatocytic anoxia/reoxygenation and at 1 and 4 hours following partial warm 60 min liver I-R in vivo in rats [47] and, after Chloroquine treatment, liver I-R injuries were aggravated at these time points studied [47].

HMGB1 has also an important functional role in cross-regulating apoptosis and autophagy [80]. Actively secreted by nonparenchymal liver cells, Kupffer, and sinusoidal endothelial cells and/or passively released by necrotic liver cells [84, 85], the stress sensor with redox activity HMGB1 acts as protein signal that initiates the inflammatory response resulting from liver I-R [87]. For HMGB1 translocation from nuclei to cytoplasm and for enhanced autophagy, ROS signals are required [122]. Following 45 min warm partial liver I-R injury in mice, HMGB1 translocated from the nucleus to the cytoplasm of hepatocytes, competitively combined with Beclin 1 and promoted the levels of autophagy through representing the site of the antiapoptotic Bcl-2 protein, which normally maintains the inactive status of autophagy, and caused warm liver I-R injury in rat [46].

Ethyl-Pyruvate, a lipophilic ester derived from the endogenous metabolite pyruvate, seems to improve liver injury by inhibiting the intrinsic pathway of apoptosis and autophagy [46]. Ethyl-Pyruvate might decrease separately both apoptosis through the downregulation of the HMGB1/TLR4/NF-B axis and autophagy through competitive interaction with Beclin 1 [46]. In fact, following 45 min warm partial liver I-R injury in mice, stressed hepatocytes released HMGB1 [46]. When animals were treated with Ethyl-Pyruvate, liver injury, apoptosis, and necrosis were decreased as a result of HMGB1 downregulation and autophagy was inhibited through the competitive interaction of HMGB1 with Beclin 1 [46].

Nevertheless, a recent study suggested that HMGB1 is not required for ATP production, cellular respiration, mitochondrial architecture, or autophagy in liver and heart [123]. In mice with conditional HMGB1 deletion, mitochondrial function and liver and heart autophagy were not affected [123]. Other studies again outline the key role of HMGB1 in mitochondrial quality control and autophagy [124–126]. In particular, an aggravation of liver I-R injury after HMGB1 depletion has been reported. In fact, genetic deletion of HMGB1 from hepatocytes resulted in enhanced inflammatory signaling, led to nuclear instability with increased DNA damage and histone release, led to mitochondria damage by exhausting nicotinamide adenine (NAD) and ATP stores, exhibited increased ROS production, and finally increased cell death [126]. In mice, fasting for one day protected from 60 min warm liver I-R injury via Sirt1-dependent downregulation of circulating HMGB1 [127]. The reduced levels of circulating HGMB1 damped the activation and self-propagation of Kupffer cells and hence protected from liver I-R [127].

3.3. Protective or Detrimental Role of Autophagy against Warm and/or Cold Liver I-R Injury: Various Drugs and Different Methods for Monitoring Autophagy in Different Animal and Human Experimental Liver Warm and/or Cold I-R Models

How pharmacological and surgical modulation of liver autophagy could protect from or promote liver injury following I-R remains to be clarified, as the studies on this subject report either downregulated or excessive levels of liver autophagy. At this point, it is important to mention that the methods used for measuring autophagy were mainly steady state methods, the drugs used to modulate liver autophagy were not entirely specific for inhibition or stimulation of autophagy, and the animal and human experimental liver I-R models differed considerably. In order to study the effects of autophagy modulation on warm and/or cold liver I-R injury both animal experimental liver I-R models and human experimental I-R models are used. The common length of partial warm ischemia in rodent models was usually 30, 45, 60 or 90 min [128]. In agreement with this, as shown in Table 2, in most of studies, the role of autophagy on liver I-R injury in rodents has been evaluated by using 60 min partial lobar (70%) liver warm ischemia model [28, 32, 37, 42, 44, 47, 48]. The model of partial lobar (70%) liver ischemia includes interruption of blood flow to the left lateral and median liver lobes leaving the right lobe for decompression [129]. As animal studies overall mimic real clinic conditions in which liver surgery and liver transplantation are performed in humans, they permit to draw conclusions with certain relevance for the human physiopathology.

3.3.1. Methods for Monitoring Autophagy

Accumulation of autophagosomes may be due to both the induction of autophagy and the blockage of a late step of the autophagy process, including impaired autophagosome-lysosome fusion and compromised lysosomal activity [130]. Induction of autophagy, assessed by steady state methods, does not allow a determination of whether the autophagic process goes to completion [56]. Incomplete autophagy, which would lead to the accumulation of autophagosomes, may contribute to cellular and organ dysfunction, whereas complete autophagy will generally exert a cytoprotective effect [56]. As steady state methods evaluate autophagy only at a certain time point [56], they may not reflect properly the autophagic activity [56]. Actually, Table 2 shows that most studies on warm and/or cold liver I-R [26, 28–33, 35–42, 44, 46] used steady state methods: electron microscopy, Atg8/LC3 western blotting and ubiquitin-like protein conjugation systems, fluorescence microscopy for monitoring phagophore, and autophagosome formation.

Electron Microscopy. The autophagosome is a transient organelle existing for less than 10 min before fusing with the lysosome, resulting in the appearance of autophagolysosomes at various stages of degradation [131]. Electron microscopy can visualize early-stage autophagosomes but is less sensitive for the visualization of late-stage autophagosomes [132]. So the isolated approach with electron microscopy is not sufficient to evaluate autophagy levels [56].

LC3 Western Blotting. LC3-II is present in most of the autophagic steps and reliably associated with phagophores, sealed autophagosomes and mature autophagosomes/autolysosomes [133]. It is widely used to monitor autophagy. Immunoblot analysis detects the conversion of LC3-I to LC3-II; the amount of LC3-II is clearly correlated with the number of autophagosomes [134]. However, LC3-II itself is degraded by autophagy, and the amount of LC3-II at a certain time point does not necessarily indicate autophagic flux. Simple comparison of LC3-I and LC3-II or summation of LC3-II and LC3-II for ratio determination may not be appropriate to correctly evaluate autophagy [134]. An increased number of autophagosomes can occur despite later steps of autophagy being blocked; the quantification of LC3-II [134] before and after the inhibition of autophagosome-lysosome fusion by using lysosomal inhibitors may indicate more accurately the autophagic flux [134]. Chloroquine and hydroxychloroquine increase the pH of the lysosome; Bafilomycin A1 inhibits the lysosomal Na⁺H⁺ ATPase; in this way, they prevent the activity of lysosomal acid proteases and cause autophagosomes to accumulate. Similar effects are induced by treatment with specific inhibitors of lysosomal proteases, such as Pepstatin A and/or E64d [134]. In this case, the real autophagic flux is represented by the different amounts of LC3-II in the samples in the absence or presence of lysosomal proteases inhibitors. LC3-II levels proportionally increase in treated versus untreated samples [134].

Ubiquitin-Like Protein Conjugation Systems. The p62 (SQSTM1/sequestosome 1) is a ubiquitin-binding scaffold protein that can bind LC3 [135]. This protein accumulates when autophagy is inhibited and decreases when autophagy is induced [136]. In some studies on warm or cold liver I-R injury in rats, autophagy was monitored by degradation of p62 using Western blot method [41, 42, 44]. However, p62 is regulated at the transcriptional level by oxidative stress and by Ras oncogene and also feeds back to regulate NF-B activity [136]. As p62 levels may be changed independently from autophagy; additional methods to validate changes in protein aggregate turnover by autophagy are necessary [136–138].

Fluorescence Microscopy. The fluorescent-based method with the green fluorescent protein- (GFP-) LC3 counting the GFP-LC3 puncta uses the fact that, after autophagy induction, LC3B becomes part of the newly formed autophagosomes and that GFP-LC3 changes its cellular localization from a diffuse cytosolic pattern to a punctate pattern. Once again, as steady state measurement, this method is not sufficient to measure autophagy, when used as an isolated approach [56].

Autophagy is a dynamic process of bulk degradation of cellular proteins and organelles in lysosomes [139]. Autophagic substrates need to be monitored to verify that they have reached these organelles and eventually degraded [56]. Evaluation of the autophagic flux, a complete process of autophagy including the delivery of cargo to lysosomes, via its fusion with autophagosomes or amphisomes and its subsequent breakdown and recycling, [56] is important to determine whether drugs and/or surgical techniques truly affect autophagy. As shown in Table 2, only a few studies have monitored the autophagic flux in order to evaluate the extent of autophagy [27, 34, 43, 45, 47, 48].

3.3.2. Side Effects of Chemical Autophagy Stimulators or Inhibitors

The chemical stimulators and inhibitors of autophagy used actually are not specific and may have a series of additional effects on liver I-R apart from their action on autophagy.

(1) Chemical Stimulators of Autophagy. Inducing, increasing, or restoring basal autophagic activity in certain cell types as the hepatocytes, following warm and/or cold liver I-R, might be of therapeutic benefit. As shown in Table 2, the modulation of autophagy by some stimulators protected against liver I-R injury [27, 28, 32, 34, 37, 38, 41, 42, 45]. However, the unspecificity of the used drugs renders the interpretation of the results difficult.

Rapamycin, an autophagy inducer by inhibiting the mTOR pathway, plays a central role in several important cellular processes other than autophagy [140]. Interfering with the translation of HIF-1α, it has an antiangiogenic effect, and inhibiting the phosphorylation of BAD by S6 K1 Rapamycin may promote apoptosis [140]. So its protective effects in 90 min warm liver I-R injury in mice may be partly due to Akt1 activation and decreased apoptosis by H₂S associated copretreatment [38]. Similarly Rosiglitazone, another autophagy stimulator, has shown additional protective effects (increase of ATP levels and the inhibition of Caspase-3 activation) in 30, 60, and 90 min liver I-R injury in old mice that cannot be accounted to the increase of autophagy [28].

The IMPase inhibitors, Lithium chloride and Carbamazepine, can induce autophagy [92]. They have also shown additional protective effects against liver I-R injury other than autophagy induction [42, 45]. Lithium chloride showed multiple additional effects, the decrease of HMGB1 and proinflammatory cytokines levels, the modulation of MAPK activation, and the inhibition of Caspase-3 and Caspase-7 activation [42]. The second, Carbamazepine, suppressed both calcium overloading and uncontrolled Calpain activation [45]. In a murine model of 60 min liver I-R Cisplatin treatment increased liver autophagy and protected against I-R injury [32]. Although the beneficial effects of Cisplatin are not only the result of autophagy stimulation but also of decreased HMGB1 and proinflammatory cytokines levels and of the modulation of MAPK activation [32].

In steatotic rat livers that were preserved in cold solution for 24 hours, autophagy was decreased [41]. A close relationship between 5′ AMP-activated protein kinase (AMPK) activation and endoplasmic reticulum (ER) stress and autophagy has been observed in these livers [41]. The addition of a Melatonin and Trimetazidine cocktail to the cold preservation solution improved steatotic liver graft preservation through AMPK activation, which in turn reduced ER stress and increased autophagy [41]. However, these beneficial effects of the Melatonin and Trimetazidine cocktail may be due in part to a reduction of apoptotic liver cells mainly observed in periportal and midzonal areas of the liver [41].

In human liver surgery and transplantation, the improvement of clinical outcomes by the use of IP of the liver was associated to higher levels of autophagy. However, the decrease of ER stress [35] and the increase of ATP and Beclin 1 levels observed after IP of the liver may have been responsible too for the beneficial effects of this surgical strategy [29].

(2) Chemical Inhibitors of Autophagy. Similar to autophagy stimulators, autophagy inhibitors are not specific [33, 39, 43, 44] and additional effects of these drugs may play an important role [43, 44, 46–48].

Autophagy inhibition by 3-MA in human hypoxemic/reoxygenated hepatocytes resulted in MPT lowering and onset of apoptosis [39]. Autophagy inhibition by LY294002 and Wortmannin during liver transplantation in rats reduced liver graft dysfunction and mortality rate of transplanted animals [33].

The PI3K inhibitors, 3-MA, LY294002, and Wortmannin, typically block Class III PI3Ks, which act as downstream of the negative regulatory Class I kinase. However, their inhibitory action on autophagy differs [141]. In fact 3-MA may promote or suppress autophagic flux [142], whereas Wortmannin seems to have inhibitory effects opposite to those of 3-MA. It has persistent effects on class III PI3K, an autophagy activator, but also it has transient effects on class I PI3K, which is an autophagy inhibitor [142]. The autophagic inhibitor LY294002 plays also a dual role in the regulation of autophagy, as it may activate autophagy by inhibiting the class I PI3K [143] and as it modulates calcium overloading, Calpain activation, and MPT, all implicated in the development of warm liver I-R injury [77, 81].

Also Melatonin, Ethyl-Pyruvate, and Chloroquine, all three autophagy inhibitors, present additional protective effects against liver I-R injury. Melatonin in fact may decrease liver apoptosis [48], Ethyl-Pyruvate may inhibit HMGB1/TLR4/NF-B axis inducing apoptosis [46] and Chloroquine, which has protective effects in the early reperfusion phase after 60 and 90 min warm liver ischemia, may modulate MAPK activation [44].

Autophagy inhibition by Chloroquine pretreatment increased mitochondrial oxidative stress and hepatocellular necrosis following 90 min warm liver I-R in rats [43]. Antioxidant NAC pretreatment again diminished the ischemia-induced liver injury of these rats, which received also Chloroquine treatment. However, the beneficial effects against liver injury by NAC seem to be due also to decreased mitochondrial ROS-inducing necrosis [43].

4. Conclusion

The pathogenesis of warm and/or cold liver I-R injury represents a complex interplay between necrosis, apoptosis, and autophagy. It seems that stimulation of autophagy plays a more important role during liver reperfusion than ischemia. Depending on the context, induction or impairment of autophagy during warm and/or cold liver I-R can be protective or detrimental for liver cells. Stimulation of impaired autophagy following warm and/or cold I-R may promote hepatocyte survival by degradation of intracellular contents to maintain ATP production and removal of damaged organelles and protein aggregates. Excessive and long-term upregulation of autophagy, as it occurs during severe ischemic insult of the liver, may lead to destruction of essential proteins and organelles resulting in hepatocellular apoptosis and necrosis.

However, the results of the studies on autophagy during warm and/or cold liver I-R remain discordant. This may be due to several factors, namely, the lack of drugs which exert specific and exclusive autophagic stimulation or inhibition, the different experimental liver I-R models used, and the different methods of autophagy evaluation. So how pharmacological and/or surgical modulation of liver autophagy could protect from or promote liver injury following warm and/or cold I-R remains to be clarified. Large animal studies on liver I-R, also at a genetic level with knockout models, which provide a very specific targeted disruption of a particular autophagic protein and will therefore be more informative than the use of not entirely specific chemical stimulators or inhibitors of the same autophagic protein, are needed. Last but not least the methods for monitoring autophagy should preferentially measure the autophagic flux.

In any way, the autophagic cell response to warm and/or cold liver I-R may provide an additional time to the cell death processes, delaying apoptosis and necrosis, and thus ultimately increasing the possibility for novel therapeutic intervention to diminish the extent of warm/cold liver I-R injury.

Conflict of Interests

The authors declare that there is no conflict of interests regarding the publication of this paper.

References

H. Jaeschke, “Mechanisms of reperfusion injury after warm ischemia of the liver,” Journal of Hepato-Biliary-Pancreatic Surgery, vol. 5, no. 4, pp. 402–408, 1998.
View at: Publisher Site | Google Scholar
R. Cursio, “Caspase inhibition in liver transplantation: from basic research to clinical studies,” HPB, vol. 12, no. 1, pp. 1–3, 2010.
View at: Publisher Site | Google Scholar
H. Jaeschke, “Molecular mechanisms of hepatic ischemia-reperfusion injury and preconditioning,” American Journal of Physiology—Gastrointestinal and Liver Physiology, vol. 284, no. 1, pp. G15–G26, 2003.
View at: Google Scholar
R. Cursio, Liver ischemia-reperfusion injury in the rat: role of nonparenchymal liver cells [Postdoctoral thesis on liver transplantation], University of Paris XI, Paris, France, 2002.
G. C. Velmahos, K. Toutouzas, R. Radin et al., “High success with nonoperative management of blunt hepatic trauma: the liver is a sturdy organ,” Archives of Surgery, vol. 138, no. 5, pp. 475–481, 2003.
View at: Publisher Site | Google Scholar
H. T. Hassoun, B. C. Kone, D. W. Mercer, F. G. Moody, N. W. Weisbrodt, and F. A. Moore, “Post-injury multiple organ failure: the role of the gut,” Shock, vol. 15, no. 1, pp. 1–10, 2001.
View at: Google Scholar
J. Belghiti, K. Hiramatsu, S. Benoist, P. P. Massault, A. Sauvanet, and O. Farges, “Seven hundred forty-seven hepatectomies in the 1990s: an update to evaluate the actual risk of liver resection,” Journal of the American College of Surgeons, vol. 191, no. 1, pp. 38–46, 2000.
View at: Publisher Site | Google Scholar
P.-A. Clavien, M. Selzner, H. A. Rüdiger et al., “A prospective randomized study in 100 consecutive patients undergoing major liver resection with versus without ischemic preconditioning,” Annals of Surgery, vol. 238, no. 6, pp. 843–852, 2003.
View at: Publisher Site | Google Scholar
P.-A. Clavien, P. R. C. Harvey, and S. M. Strasberg, “Preservation and reperfusion injuries in liver allografts: an overview and synthesis of current studies,” Transplantation, vol. 53, no. 5, pp. 957–978, 1992.
View at: Publisher Site | Google Scholar
D. G. Farmer, F. Amersi, J. Kupiec-Weglinski, and R. W. Busuttil, “Current status of ischemia and reperfusion injury in the liver,” Transplantation Reviews, vol. 14, no. 2, pp. 106–126, 2000.
View at: Publisher Site | Google Scholar
C. Fondevila, R. W. Busuttil, and J. W. Kupiec-Weglinski, “Hepatic ischemia-reperfusion injury—a fresh look,” Experimental and Molecular Pathology, vol. 74, no. 2, pp. 86–93, 2003.
View at: Publisher Site | Google Scholar
M. Glanemann, J. M. Langrehr, B. J. Stange et al., “Clinical implications of hepatic preservation injury after adult liver transplantation,” The American Journal of Transplantation, vol. 3, no. 8, pp. 1003–1009, 2003.
View at: Publisher Site | Google Scholar
O. de Rougemont, K. Lehmann, and P.-A. Clavien, “Preconditioning, organ preservation, and postconditioning to prevent ischemia-reperfusion injury to the liver,” Liver Transplantation, vol. 15, no. 10, pp. 1172–1182, 2009.
View at: Publisher Site | Google Scholar
L. Sanchez-Urdazpal, G. J. Gores, E. M. Ward et al., “Ischemic-type biliary complications after orthotopic liver transplantation,” Hepatology, vol. 16, no. 1, pp. 49–53, 1992.
View at: Publisher Site | Google Scholar
C. I. Buis, H. Hoekstra, R. C. Verdonk, and R. J. Porte, “Causes and consequences of ischemic-type biliary lesions after liver transplantation,” Journal of Hepato-Biliary-Pancreatic Surgery, vol. 13, no. 6, pp. 517–524, 2006.
View at: Publisher Site | Google Scholar
R. Cursio and J. Gugenheim, “Ischemia-reperfusion injury and ischemic-type biliary lesions following liver transplantation,” Journal of Transplantation, vol. 2012, Article ID 164329, 17 pages, 2012.
View at: Publisher Site | Google Scholar
P. F. Halloran, “Call for revolution: a new approach to describing allograft deterioration,” American Journal of Transplantation, vol. 2, no. 3, pp. 195–200, 2002.
View at: Publisher Site | Google Scholar
S. Gourishankar and P. F. Halloran, “Late deterioration of organ transplants: a problem in injury and homeostasis,” Current Opinion in Immunology, vol. 14, no. 5, pp. 576–583, 2002.
View at: Publisher Site | Google Scholar
P.-A. Clavien, “How far can we go with marginal donors?” Journal of Hepatology, vol. 45, no. 4, pp. 483–484, 2006.
View at: Publisher Site | Google Scholar
N. Selzner, H. Rudiger, R. Graf, and P.-A. Clavien, “Protective strategies against ischemic injury of the liver,” Gastroenterology, vol. 125, no. 3, pp. 917–936, 2003.
View at: Publisher Site | Google Scholar
H. Jaeschke and J. J. Lemasters, “Apoptosis versus oncotic necrosis in hepatic ischemia/reperfusion injury,” Gastroenterology, vol. 125, no. 4, pp. 1246–1257, 2003.
View at: Publisher Site | Google Scholar
J. J. Lemasters, A.-L. Nieminen, T. Qian et al., “The mitochondrial permeability transition in cell death: a common mechanism in necrosis, apoptosis and autophagy,” Biochimica et Biophysica Acta, vol. 1366, no. 1-2, pp. 177–196, 1998.
View at: Publisher Site | Google Scholar
J. J. Lemasters, “V. Necrapoptosis and the mitochondrial permeability transition: shared pathways to necrosis and apoptosis,” The American Journal of Physiology, vol. 276, no. 1, part 1, pp. G1–G6, 1999.
View at: Google Scholar
R. Cursio, J. Gugenheim, J. E. Ricci et al., “A caspase inhibitor fully protects rats against lethal normothermic liver ischemia by inhibition of liver apoptosis,” The FASEB Journal, vol. 13, no. 2, pp. 253–261, 1999.
View at: Google Scholar
W. Gao, R. C. Bentley, J. E. Madden, and P.-A. Clavien, “Apoptosis of sinusoidal endothelial cells is a critical mechanism of preservation injury in rat liver transplantation,” Hepatology, vol. 27, no. 6, pp. 1652–1660, 1998.
View at: Publisher Site | Google Scholar
Z. Lu, K. Dono, K. Gotoh et al., “Participation of autophagy in the degeneration process of rat hepatocytes after transplantation following prolonged cold preservation,” Archives of Histology and Cytology, vol. 68, no. 1, pp. 71–80, 2005.
View at: Publisher Site | Google Scholar
J.-S. Kim, T. Nitta, D. Mohuczy et al., “Impaired autophagy: a mechanism of mitochondrial dysfunction in anoxic rat hepatocytes,” Hepatology, vol. 47, no. 5, pp. 1725–1736, 2008.
View at: Publisher Site | Google Scholar
T. Shin, S. Kuboki, N. Huber et al., “Activation of peroxisome proliferator-activated receptor-γ during hepatic ischemia is age-dependent,” Journal of Surgical Research, vol. 147, no. 2, pp. 200–205, 2008.
View at: Publisher Site | Google Scholar
M.-C. Domart, D. D. Esposti, M. Sebagh et al., “Concurrent induction of necrosis, apoptosis, and autophagy in ischemic preconditioned human livers formerly treated by chemotherapy,” Journal of Hepatology, vol. 51, no. 5, pp. 881–889, 2009.
View at: Publisher Site | Google Scholar
T. Minor, J. Stegemann, A. Hirner, and M. Koetting, “Impaired autophagic clearance after cold preservation of fatty livers correlates with tissue necrosis upon reperfusion and is reversed by hypothermic reconditioning,” Liver Transplantation, vol. 15, no. 7, pp. 798–805, 2009.
View at: Publisher Site | Google Scholar
R. Cursio, P. Colosetti, M.-C. Saint-Paul et al., “Induction of different types of cell death after normothermic liver ischemia-reperfusion,” Transplantation Proceedings, vol. 42, no. 10, pp. 3977–3980, 2010.
View at: Publisher Site | Google Scholar
J. Cardinal, P. Pan, M. Ross et al., “Cisplatin prevents high mobility group box 1 release and is protective in a murine model of hepatic ischemia/reperfusion injury,” Hepatology, vol. 50, no. 2, pp. 565–574, 2009.
View at: Publisher Site | Google Scholar
K. Gotoh, Z. Lu, M. Morita et al., “Participation of autophagy in the initiation of graft dysfunction after rat liver transplantation,” Autophagy, vol. 5, no. 3, pp. 351–360, 2009.
View at: Publisher Site | Google Scholar
J. Wang, I. Ahn, T. D. Fischer et al., “Autophagy suppresses age-dependent ischemia and reperfusion injury in livers of mice,” Gastroenterology, vol. 141, no. 6, pp. 2188.e6–2199.e6, 2011.
View at: Publisher Site | Google Scholar
D. Degli Esposti, M. Sebagh, P. Pham et al., “Ischemic preconditioning induces autophagy and limits necrosis in human recipients of fatty liver grafts, decreasing the incidence of rejection episodes,” Cell Death and Disease, vol. 2, no. 1, article e111, 2011.
View at: Publisher Site | Google Scholar
T. Minor, M. Koetting, G. Kaiser, P. Efferz, B. Lüer, and A. Paul, “Hypothermic reconditioning by gaseous oxygen improves survival after liver transplantation in the pig,” American Journal of Transplantation, vol. 11, no. 12, pp. 2627–2634, 2011.
View at: Publisher Site | Google Scholar
J. Evankovich, R. Zhang, J. S. Cardinal et al., “Calcium/calmodulin-dependent protein kinase IV limits organ damage in hepatic ischemia-reperfusion injury through induction of autophagy,” American Journal of Physiology—Gastrointestinal and Liver Physiology, vol. 303, no. 2, pp. G189–G198, 2012.
View at: Publisher Site | Google Scholar
D. Wang, Y. Ma, Z. Li et al., “The role of AKT1 and autophagy in the protective effect of hydrogen sulphide against hepatic ischemia/reperfusion injury in mice,” Autophagy, vol. 8, no. 6, pp. 954–962, 2012.
View at: Publisher Site | Google Scholar
R. H. Bhogal, C. J. Weston, S. M. Curbishley, D. H. Adams, and S. C. Afford, “Autophagy: a cyto-protective mechanism which prevents primary human hepatocyte apoptosis during oxidative stress,” Autophagy, vol. 8, no. 4, pp. 545–558, 2012.
View at: Publisher Site | Google Scholar
J. Gracia-Sancho, H. García-Calderó, D. Hide et al., “Simvastatin maintains function and viability of steatotic rat livers procured for transplantation,” Journal of Hepatology, vol. 58, no. 6, pp. 1140–1146, 2013.
View at: Publisher Site | Google Scholar
M. A. Zaouali, E. Boncompagni, R. J. Reiter et al., “AMPK involvement in endoplasmic reticulum stress and autophagy modulation after fatty liver graft preservation: a role for melatonin and trimetazidine cocktail,” Journal of Pineal Research, vol. 55, no. 1, pp. 65–78, 2013.
View at: Publisher Site | Google Scholar
A. Liu, H. Fang, U. Dahmen, and O. Dirsch, “Chronic lithium treatment protects against liver ischemia/reperfusion injury in rats,” Liver Transplantation, vol. 19, no. 7, pp. 762–772, 2013.
View at: Publisher Site | Google Scholar
K. Sun, X. Xie, Y. Liu et al., “Autophagy lessens ischemic liver injury by reducing oxidative damage,” Cell & Bioscience, vol. 3, article 26, 2013.
View at: Publisher Site | Google Scholar
H. Fang, A. Liu, U. Dahmen, and O. Dirsch, “Dual role of chloroquine in liver ischemia reperfusion injury: reduction of liver damage in early phase, but aggravation in late phase,” Cell Death & Disease, vol. 4, article e694, 2013.
View at: Publisher Site | Google Scholar
J.-S. Kim, J.-H. Wang, T. G. Biel et al., “Carbamazepine suppresses calpain-mediated autophagy impairment after ischemia/reperfusion in mouse livers,” Toxicology and Applied Pharmacology, vol. 273, no. 3, pp. 600–610, 2013.
View at: Publisher Site | Google Scholar
M. Shen, J. Lu, W. Dai et al., “Ethyl pyruvate ameliorates hepatic ischemia-reperfusion injury by inhibiting intrinsic pathway of apoptosis and autophagy,” Mediators of Inflammation, vol. 2013, Article ID 461536, 12 pages, 2013.
View at: Publisher Site | Google Scholar
N. Yun, H.-I. Cho, and S.-M. Lee, “Impaired autophagy contributes to hepatocellular damage during ischemia/reperfusion: heme oxygenase-1 as a possible regulator,” Free Radical Biology and Medicine, vol. 68, pp. 168–177, 2014.
View at: Publisher Site | Google Scholar
J.-W. Kang, H.-I. Cho, and S.-M. Lee, “Melatonin inhibits mTOR-dependent autophagy during liver ischemia/reperfusion,” Cellular Physiology and Biochemistry, vol. 33, no. 1, pp. 23–36, 2014.
View at: Publisher Site | Google Scholar
E. H. Baehrecke, “Autophagy: dual roles in life and death?” Nature Reviews. Molecular Cell Biology, vol. 6, no. 6, pp. 505–510, 2005.
View at: Publisher Site | Google Scholar
D. J. Klionsky, “The molecular machinery of autophagy: unanswered questions,” Journal of Cell Science, vol. 118, no. 1, pp. 7–18, 2005.
View at: Publisher Site | Google Scholar
Y. Chen and D. J. Klionsky, “The regulation of autophagy—unanswered questions,” Journal of Cell Science, vol. 124, no. 2, pp. 161–170, 2011.
View at: Publisher Site | Google Scholar
P.-E. Rautou, A. Mansouri, D. Lebrec, F. Durand, D. Valla, and R. Moreau, “Autophagy in liver diseases,” Journal of Hepatology, vol. 53, no. 6, pp. 1123–1134, 2010.
View at: Publisher Site | Google Scholar
P. Codogno and A. J. Meijer, “Autophagy in the liver,” Journal of Hepatology, vol. 59, no. 2, pp. 389–391, 2013.
View at: Publisher Site | Google Scholar
M. J. Czaja, W.-X. Ding, T. M. Donohue Jr. et al., “Functions of autophagy in normal and diseased liver,” Autophagy, vol. 9, no. 8, pp. 1131–1158, 2013.
View at: Publisher Site | Google Scholar
X.-M. Yin, W.-X. Ding, and W. Gao, “Autophagy in the liver,” Hepatology, vol. 47, no. 5, pp. 1773–1785, 2008.
View at: Publisher Site | Google Scholar
D. J. Klionski, H. Abeliovich, P. Agostinis, D. K. Agrawal, and G. Aliev, “Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes,” Autophagy, vol. 4, no. 2, pp. 151–175, 2008.
View at: Google Scholar
R. G. Thurman, I. Marzi, G. Seitz, J. Thies, J. J. Lemasters, and F. Zimmerman, “Hepatic reperfusion injury following orthotopic liver transplantation in the rat,” Transplantation, vol. 46, no. 4, pp. 502–506, 1988.
View at: Publisher Site | Google Scholar
C. M. B. McKeown, V. Edwards, M. J. Phillips, P. R. C. Harvey, C. N. Petrunka, and S. M. Strasberg, “Sinusoidal lining cell damage: the critical injury in cold preservation of liver allografts in the rat,” Transplantation, vol. 46, no. 2, pp. 178–191, 1988.
View at: Publisher Site | Google Scholar
J. C. Caldwell-Kenkel, R. T. Currin, Y. Tanaka, R. G. Thurman, and J. J. Lemasters, “Reperfusion injury to endothelial cells following ischemic storage of rat livers,” Hepatology, vol. 10, no. 3, pp. 292–299, 1989.
View at: Publisher Site | Google Scholar
M. Mendes-Braz, M. Elias-Miró, M. B. Jiménez-Castro, A. Casillas-Ramírez, F. S. Ramalho, and C. Peralta, “The current state of knowledge of hepatic ischemia-reperfusion injury based on its study in experimental models,” Journal of Biomedicine and Biotechnology, vol. 2012, Article ID 298657, 20 pages, 2012.
View at: Publisher Site | Google Scholar
J. J. Lemasters and R. G. Thurman, “Reperfusion injury after liver preservation for transplantation,” Annual Review of Pharmacology and Toxicology, vol. 37, pp. 327–338, 1997.
View at: Publisher Site | Google Scholar
E. E. Montalvo-Jave, T. Escalante-Tattersfield, J. A. Ortega-Salgado, E. Piña, and D. A. Geller, “Factors in the pathophysiology of the liver ischemia-reperfusion injury,” Journal of Surgical Research, vol. 147, no. 1, pp. 153–159, 2008.
View at: Publisher Site | Google Scholar
H. Jaeschke, A. Farhood, A. P. Bautista, Z. Spolarics, and J. J. Spitzer, “Complement activates Kupffer cells and neutrophils during reperfusion after hepatic ischemia,” American Journal of Physiology—Gastrointestinal and Liver Physiology, vol. 264, no. 4, part 1, pp. G801–G809, 1993.
View at: Google Scholar
H. Jaeschke, “Mechanisms of liver injury. II. Mechanisms of neutrophil-induced liver cell injury during hepatic ischemia-reperfusion and other acute inflammatory conditions,” The American Journal of Physiology—Gastrointestinal and Liver Physiology, vol. 290, no. 6, pp. G1083–G1088, 2006.
View at: Publisher Site | Google Scholar
N. A. Essani, G. M. McGuire, A. M. Manning, and H. Jaeschke, “Endotoxin-induced activation of the nuclear transcription factor κB and expression of E-selectin messenger RNA in hepatocytes, kupffer cells, and endothelial cells in vivo,” The Journal of Immunology, vol. 156, no. 8, pp. 2956–2963, 1996.
View at: Google Scholar
T. Matsumura, A. Ito, T. Takii, H. Hayashi, and K. Onozaki, “Endotoxin and cytokine regulation of toll-like receptor (TLR) 2 and TLR4 gene expression in murine liver and hepatocytes,” Journal of Interferon and Cytokine Research, vol. 20, no. 10, pp. 915–921, 2000.
View at: Publisher Site | Google Scholar
N. C. Teoh, “Hepatic ischemia reperfusion injury: contemporary perspectives on pathogenic mechanisms and basis for hepatoprotection-the good, bad and deadly,” Journal of Gastroenterology and Hepatology, vol. 26, supplement 1, pp. 180–187, 2011.
View at: Publisher Site | Google Scholar
B. Vollmar, J. Glasz, R. Leiderer, S. Post, and M. D. Menger, “Hepatic microcirculatory perfusion failure is a determinant of liver dysfunction in warm ischemia-reperfusion,” The American Journal of Pathology, vol. 145, no. 6, pp. 1421–1431, 1994.
View at: Google Scholar
W. Zhou, M. O. McCollum, B. A. Levine, and M. S. Olson, “Inflammation and platelet-activating factor production during hepatic ischemia/reperfusion,” Hepatology, vol. 16, no. 5, pp. 1236–1240, 1992.
View at: Publisher Site | Google Scholar
X. Qin and B. Gao, “The complement system in liver diseases,” Cellular & Molecular Immunology, vol. 3, no. 5, pp. 333–340, 2006.
View at: Google Scholar
P. Boros and J. S. Bromberg, “New cellular and molecular immune pathways in ischemia/reperfusion injury,” The American Journal of Transplantation, vol. 6, no. 4, pp. 652–658, 2006.
View at: Publisher Site | Google Scholar
Y. Zhai, R. W. Busuttil, and J. W. Kupiec-Weglinski, “Liver ischemia and reperfusion injury: new insights into mechanisms of innate-adaptive immune-mediated tissue inflammation,” American Journal of Transplantation, vol. 11, no. 8, pp. 1563–1569, 2011.
View at: Publisher Site | Google Scholar
Y. Zhai, H. Petrowsky, J. C. Hong, R. W. Busuttil, and J. W. Kupiec-Weglinski, “Ischaemia-reperfusion injury in liver transplantation-from bench to bedside,” Nature Reviews Gastroenterology and Hepatology, vol. 10, no. 2, pp. 79–89, 2013.
View at: Publisher Site | Google Scholar
Y. Huang, H. Rabb, and K. L. Womer, “Ischemia-reperfusion and immediate T cell responses,” Cellular Immunology, vol. 248, no. 1, pp. 4–11, 2007.
View at: Publisher Site | Google Scholar
D. Linfert, T. Chowdhry, and H. Rabb, “Lymphocytes and ischemia-reperfusion injury,” Transplantation Reviews, vol. 23, no. 1, pp. 1–10, 2009.
View at: Publisher Site | Google Scholar
C. C. Caldwell, T. Okaya, A. Martignoni, T. Husted, R. Schuster, and A. B. Lentsch, “Divergent functions of CD4⁺ T lymphocytes in acute liver inflammation and injury after ischemia-reperfusion,” American Journal of Physiology—Gastrointestinal and Liver Physiology, vol. 289, no. 5, pp. G969–G976, 2005.
View at: Publisher Site | Google Scholar
J.-S. Kim, T. Qian, and J. J. Lemasters, “Mitochondrial permeability transition in the switch from necrotic to apoptotic cell death in ischemic rat hepatocytes,” Gastroenterology, vol. 124, no. 2, pp. 494–503, 2003.
View at: Publisher Site | Google Scholar
R. Cursio, P. Colosetti, P. Auberger, and J. Gugenheim, “Autophagy and liver ischemia-reperfusion injury,” in Autophagy: Principles, Regulation and Role in Diseases, pp. 297–328, Nova, New York, NY, USA, 2012.
View at: Google Scholar
Z. Xie and D. J. Klionsky, “Autophagosome formation: core machinery and adaptations,” Nature Cell Biology, vol. 9, no. 10, pp. 1102–1109, 2007.
View at: Publisher Site | Google Scholar
R. Kang, H. J. Zeh, M. T. Lotze, and D. Tang, “The Beclin 1 network regulates autophagy and apoptosis,” Cell Death and Differentiation, vol. 18, no. 4, pp. 571–580, 2011.
View at: Publisher Site | Google Scholar
S. A. Susin, H. K. Lorenzo, N. Zamzami et al., “Molecular characterization of mitochodrial apoptosis-inducing factor,” Nature, vol. 397, no. 6718, pp. 441–446, 1999.
View at: Publisher Site | Google Scholar
S. P. Elmore, T. Qian, S. F. Grissom, and J. J. Lemasters, “The mitochondrial permeability transition initiates autophagy in rat hepatocytes,” The FASEB Journal, vol. 15, no. 12, pp. 2286–2287, 2001.
View at: Google Scholar
J. R. Klune and A. Tsung, “Molecular biology of liver ischemia/reperfusion injury: established mechanisms and recent advancements,” Surgical Clinics of North America, vol. 90, no. 4, pp. 665–677, 2010.
View at: Publisher Site | Google Scholar
I. Ito, J. Fukazawa, and M. Yoshida, “Post-translational methylation of high mobility group box 1 (HMGB1) causes its cytoplasmic localization in neutrophils,” The Journal of Biological Chemistry, vol. 282, no. 22, pp. 16336–16344, 2007.
View at: Publisher Site | Google Scholar
P. Scaffidi, T. Misteli, and M. E. Bianchi, “Release of chromatin protein HMGB1 by necrotic cells triggers inflammation,” Nature, vol. 418, no. 6894, pp. 191–195, 2002.
View at: Publisher Site | Google Scholar
S. Müller, P. Scaffidi, B. Degryse et al., “The double life of HMGB1 chromatin protein: architectural factor and extracellular signal,” The EMBO Journal, vol. 20, no. 16, pp. 4337–4340, 2001.
View at: Publisher Site | Google Scholar
A. Tsung, R. Sahai, H. Tanaka et al., “The nuclear factor HMGB1 mediates hepatic injury after murine liver ischemia-reperfusion,” Journal of Experimental Medicine, vol. 201, no. 7, pp. 1135–1143, 2005.
View at: Publisher Site | Google Scholar
A. Liu, H. Jin, O. Dirsch et al., “Release of danger signals during ischemic storage of the liver: a potential marker of organ damage?” Mediators of Inflammation, vol. 2010, Article ID 436145, 11 pages, 2010.
View at: Publisher Site | Google Scholar
A. Liu, H. Fang, O. Dirsch, H. Jin, and U. Dahmen, “Oxidation of hmgb1 causes attenuation of its pro-inflammatory activity and occurs during liver ischemia and reperfusion,” PLoS ONE, vol. 7, no. 4, Article ID e35379, 2012.
View at: Publisher Site | Google Scholar
A. Liu, O. Dirsch, H. Fang et al., “HMGB1 in ischemic and non-ischemic liver after selective warm ischemia/reperfusion in rat,” Histochemistry and Cell Biology, vol. 135, no. 5, pp. 443–452, 2011.
View at: Publisher Site | Google Scholar
M. Ilmakunnas, E. M. Tukiainen, A. Rouhiainen et al., “High mobility group box 1 protein as a marker of hepatocellular injury in human liver transplantation,” Liver Transplantation, vol. 14, no. 10, pp. 1517–1525, 2008.
View at: Publisher Site | Google Scholar
S. Sarkar, R. A. Floto, Z. Berger et al., “Lithium induces autophagy by inhibiting inositol monophosphatase,” The Journal of Cell Biology, vol. 170, no. 7, pp. 1101–1111, 2005.
View at: Publisher Site | Google Scholar
C. J. Mullonkal and L. H. Toledo-Pereyra, “Akt in ischemia and reperfusion,” Journal of Investigative Surgery, vol. 20, no. 3, pp. 195–203, 2007.
View at: Publisher Site | Google Scholar
C. Müller, F. Dünschede, E. Koch, A. M. Vollmar, and A. K. Kiemer, “α-lipoic acid preconditioning reduces ischemia-reperfusion injury of the rat liver via the PI3-kinase/Akt pathway,” The American Journal of Physiology—Gastrointestinal and Liver Physiology, vol. 285, no. 4, pp. G769–G778, 2003.
View at: Google Scholar
R. Cursio, N. Filippa, C. Miele, E. Van Obberghen, and J. Gugenheim, “Involvement of protein kinase B and mitogen-activated protein kinases in experimental normothermic liver ischaemia-reperfusion injury,” The British Journal of Surgery, vol. 93, no. 6, pp. 752–761, 2006.
View at: Publisher Site | Google Scholar
X. L. Li, K. Man, K. T. Ng, C. K. Sun, C. M. Lo, and S. T. Fan, “The influence of phosphatidylinositol 3-kinase/Akt pathway on the ischemic injury during rat liver graft preservation,” American Journal of Transplantation, vol. 5, no. 6, pp. 1264–1275, 2005.
View at: Publisher Site | Google Scholar
Y. Kurihara, T. Kanki, Y. Aoki et al., “Mitophagy plays an essential role in reducing mitochondrial production of reactive oxygen species and mutation of mitochondrial DNA by maintaining mitochondrial quantity and quality in yeast,” The Journal of Biological Chemistry, vol. 287, no. 5, pp. 3265–3272, 2012.
View at: Publisher Site | Google Scholar
A. M. Cuervo, E. Bergamini, U. T. Brunk, W. Dröge, M. Ffrench, and A. Terman, “Autophagy and aging: the importance of maintaining “clean” cells,” Autophagy, vol. 1, no. 3, pp. 131–140, 2005.
View at: Publisher Site | Google Scholar
S. Kuboki, T. Shin, N. Huber et al., “Peroxisome proliferator-activated receptor-γ protects against hepatic ischemia/reperfusion injury in mice,” Hepatology, vol. 47, no. 1, pp. 215–224, 2008.
View at: Publisher Site | Google Scholar
V. E. de Meijer, B. T. Kalish, M. Puder, and J. N. M. IJzermans, “Systematic review and meta-analysis of steatosis as a risk factor in major hepatic resection,” British Journal of Surgery, vol. 97, no. 9, pp. 1331–1339, 2010.
View at: Publisher Site | Google Scholar
D. J. Verran, T. Kusyk, D. Painter et al., “Clinical experience gained from the use of 120 steatotic donor livers for orthotopic liver transplantation,” Liver Transplantation, vol. 9, no. 5, pp. 500–505, 2003.
View at: Publisher Site | Google Scholar
P. Caraceni, C. Bianchi, M. Domenicali et al., “Impairment of mitochondrial oxidative phosphorylation in rat fatty liver exposed to preservation-reperfusion injury,” Journal of Hepatology, vol. 41, no. 1, pp. 82–88, 2004.
View at: Publisher Site | Google Scholar
M. J. J. Chu, A. J. R. Hickey, A. R. J. Phillips, and A. S. J. R. Bartlett, “The impact of hepatic steatosis on hepatic ischemia-reperfusion injury in experimental studies: a systematic review,” BioMed Research International, vol. 2013, Article ID 192029, 12 pages, 2013.
View at: Publisher Site | Google Scholar
Y. Wang, R. Singh, Y. Xiang, and M. J. Czaja, “Macroautophagy and chaperone-mediated autophagy are required for hepatocyte resistance to oxidant stress,” Hepatology, vol. 52, no. 1, pp. 266–277, 2010.
View at: Publisher Site | Google Scholar
R. Singh, S. Kaushik, Y. Wang et al., “Autophagy regulates lipid metabolism,” Nature, vol. 458, no. 7242, pp. 1131–1135, 2009.
View at: Publisher Site | Google Scholar
T. Minor, S. Akbar, R. Tolba, and F. Dombrowski, “Cold preservation of fatty liver grafts: prevention of functional and ultrastructural impairments by venous oxygen persufflation,” Journal of Hepatology, vol. 32, no. 1, pp. 105–111, 2000.
View at: Google Scholar
T. Minor and M. Kötting, “Gaseous oxygen for hypothermic preservation of predamaged liver grafts: fuel to cellular homeostasis or radical tissue alteration?” Cryobiology, vol. 40, no. 2, pp. 182–186, 2000.
View at: Publisher Site | Google Scholar
R. Scherz-Shouval, Y. Sagiv, H. Shorer, and Z. Elazar, “The COOH terminus of GATE-16, an intra-golgi transport modulator, is cleaved by the human cysteine protease HsApg4A,” The Journal of Biological Chemistry, vol. 278, no. 16, pp. 14053–14058, 2003.
View at: Publisher Site | Google Scholar
C. Peralta, G. Hotter, D. Closa, E. Gelpí, O. Bulbena, and J. Roselló-Catafau, “Protective effect of preconditioning on the injury associated to hepatic ischemia-reperfusion in the rat: role of nitric oxide and adenosine,” Hepatology, vol. 25, no. 4, pp. 934–937, 1997.
View at: Publisher Site | Google Scholar
P.-A. Clavien, S. Yadav, D. Sindram, and R. C. Bentley, “Protective effects of ischemic preconditioning for liver resection performed under inflow occlusion in humans,” Annals of Surgery, vol. 232, no. 2, pp. 155–162, 2000.
View at: Publisher Site | Google Scholar
H. Petrowsky, L. McCormack, M. Trujillo, M. Selzner, W. Jochum, and P.-A. Clavien, “A prospective, randomized, controlled trial comparing intermittent portal triad clamping versus ischemic preconditioning with continuous clamping for major liver resection,” Annals of Surgery, vol. 244, no. 6, pp. 921–928, 2006.
View at: Publisher Site | Google Scholar
D. Azoulay, M. Del Gaudio, P. Andreani et al., “Effects of 10 minutes of ischemic preconditioning of the cadaveric liver on the graft's preservation and function: the Ying and the Yang,” Annals of Surgery, vol. 242, no. 1, pp. 133–139, 2005.
View at: Publisher Site | Google Scholar
K. S. Gurusamy, Y. Kumar, D. Sharma, and B. R. Davidson, “Ischaemic preconditioning for liver transplantation,” The Cochrane Database of Systematic Reviews, vol. 21, no. 1, Article ID CD006315, 2008.
View at: Google Scholar
N. Selzner, M. Boehnert, and M. Selzner, “Preconditioning, postconditioning, and remote conditioning in solid organ transplantation: basic mechanisms and translational applications,” Transplantation Reviews, vol. 26, no. 2, pp. 115–124, 2012.
View at: Publisher Site | Google Scholar
S. O'Neill, S. Leuschner, S. J. McNally, O. J. Garden, S. J. Wigmore, and E. M. Harrison, “Meta-analysis of ischaemic preconditioning for liver resections,” The British Journal of Surgery, vol. 100, no. 13, pp. 1689–1700, 2013.
View at: Publisher Site | Google Scholar
F. G. Fernandez, J. Ritter, J. W. Goodwin, D. C. Linehan, W. G. Hawkins, and S. M. Strasberg, “Effect of steatohepatitis associated with irinotecan or oxaliplatin pretreatment on resectability of hepatic colorectal metastases,” Journal of the American College of Surgeons, vol. 200, no. 6, pp. 845–853, 2005.
View at: Publisher Site | Google Scholar
K. E. Behrns, G. G. Tsiotos, N. F. DeSouza, M. K. Krishna, J. Ludwig, and D. M. Nagorney, “Hepatic steatosis as a potential risk factor for major hepatic resection,” Journal of Gastrointestinal Surgery, vol. 2, no. 3, pp. 292–298, 1998.
View at: Publisher Site | Google Scholar
Y. Matsui, H. Takagi, X. Qu et al., “Distinct roles of autophagy in the heart during ischemia and reperfusion: roles of AMP-activated protein kinase and beclin 1 in mediating autophagy,” Circulation Research, vol. 100, no. 6, pp. 914–922, 2007.
View at: Publisher Site | Google Scholar
M. Vairetti, A. Ferrigno, R. Bertone et al., “Exogenous melatonin enhances bile flow and ATP levels after cold storage and reperfusion in rat liver: implications for liver transplantation,” Journal of Pineal Research, vol. 38, no. 4, pp. 223–230, 2005.
View at: Publisher Site | Google Scholar
I. Freitas, V. Bertone, C. Guarnaschelli et al., “In situ demonstration of improvement of liver mitochondria function by melatonin after cold ischemia,” In Vivo, vol. 20, no. 2, pp. 229–237, 2006.
View at: Google Scholar
L. Russo, J. Gracia-Sancho, H. García-Calderó et al., “Addition of simvastatin to cold storage solution prevents endothelial dysfunction in explanted rat livers,” Hepatology, vol. 55, no. 3, pp. 921–930, 2012.
View at: Publisher Site | Google Scholar
R. Kang, K. M. Livesey, H. J. Zeh, M. T. Lotze, and D. Tang, “HMGB1: a novel Beclin 1-binding protein active in autophagy,” Autophagy, vol. 6, no. 8, pp. 1209–1211, 2010.
View at: Publisher Site | Google Scholar
P. P. Huebener, G.-E. Y. Gwak, J.-P. Pradere et al., “High-mobility group box 1 is dispensable for autophagy, mitochondrial quality control, and organ function in vivo,” Cell Metabolism, vol. 19, pp. 539–547, 2014.
View at: Google Scholar
D. Tang, R. Kang, K. M. Livesey et al., “High-mobility group box 1 is essential for mitochondrial quality control,” Cell Metabolism, vol. 13, no. 6, pp. 701–711, 2011.
View at: Publisher Site | Google Scholar
R. Kang, K. M. Livesey, H. J. Zeh, M. T. Lotze, and D. Tang, “Metabolic regulation by HMGB1-mediated autophagy and mitophagy,” Autophagy, vol. 7, no. 10, pp. 1256–1258, 2011.
View at: Publisher Site | Google Scholar
H. Huang, G. W. Nace, K.-A. Mcdonald et al., “Hepatocyte-specific high-mobility group box 1 deletion worsens the injury in liver ischemia/reperfusion: a role for intracellular high-mobility group box 1 in cellular protection,” Hepatology, vol. 59, no. 5, pp. 1984–1997, 2014.
View at: Publisher Site | Google Scholar
A. Rickenbacher, J. H. Jang, P. Limani et al., “Fasting protects liver from ischemic injury through Sirt1-mediated downregulation of circulating HMGB1 in mice,” Journal of Hepatology, vol. 61, no. 2, pp. 301–308, 2014.
View at: Publisher Site | Google Scholar
T. Karatzas, A.-A. Neri, M.-E. Baibaki, and I. A. Dontas, “Rodent models of hepatic ischemia-reperfusion injury: time and percentage-related pathophysiological mechanisms,” Journal of Surgical Research, vol. 191, no. 2, pp. 399–412, 2014.
View at: Publisher Site | Google Scholar
H. U. Spiegel and R. Bahde, “Experimental models of temporary normothermic liver ischemia,” Journal of Investigative Surgery, vol. 19, no. 2, pp. 113–123, 2006.
View at: Publisher Site | Google Scholar
N. Mizushima, T. Yoshimori, and B. Levine, “Methods in mammalian autophagy research,” Cell, vol. 140, no. 3, pp. 313–326, 2010.
View at: Publisher Site | Google Scholar
Y. Ohsumi, “Historical landmarks of autophagy research,” Cell Research, vol. 24, no. 1, pp. 9–23, 2014.
View at: Publisher Site | Google Scholar
J. M. Swanlund, K. C. Kregel, and T. D. Oberley, “Investigating autophagy: quantitative morphometric analysis using electron microscopy,” Autophagy, vol. 6, no. 2, pp. 270–277, 2010.
View at: Publisher Site | Google Scholar
D. C. Rubinsztein, A. M. Cuervo, B. Ravikumar et al., “In search of an “autophagomometer”,” Autophagy, vol. 5, no. 5, pp. 585–589, 2009.
View at: Publisher Site | Google Scholar
N. Mizushima and T. Yoshimori, “How to interpret LC3 immunoblotting,” Autophagy, vol. 3, no. 6, pp. 542–545, 2007.
View at: Publisher Site | Google Scholar
M. L. Seibenhener, T. Geetha, and M. W. Wooten, “Sequestosome 1/p62—more than just a scaffold,” FEBS Letters, vol. 581, no. 2, pp. 175–179, 2007.
View at: Publisher Site | Google Scholar
J. Moscat and M. T. Diaz-Meco, “p62 at the crossroads of autophagy, apoptosis, and cancer,” Cell, vol. 137, no. 6, pp. 1001–1004, 2009.
View at: Publisher Site | Google Scholar
F. Bardag-Gorce, T. Francis, L. Nan et al., “Modifications in P62 occur due to proteasome inhibition in alcoholic liver disease,” Life Sciences, vol. 77, no. 20, pp. 2594–2602, 2005.
View at: Publisher Site | Google Scholar
K. Nakaso, Y. Yoshimoto, T. Nakano et al., “Transcriptional activation of p62/A170/ZIP during the formation of the aggregates: possible mechanisms and the role in Lewy body formation in Parkinson's disease,” Brain Research, vol. 1012, no. 1-2, pp. 42–51, 2004.
View at: Publisher Site | Google Scholar
E.-L. Eskelinen, “Maturation of autophagic vacuoles in mammalian cells,” Autophagy, vol. 1, no. 1, pp. 1–10, 2005.
View at: Google Scholar
C. M. Hartford and M. J. Ratain, “Rapamycin: something old, something new, sometimes borrowed and now renewed,” Clinical Pharmacology and Therapeutics, vol. 82, no. 4, pp. 381–388, 2007.
View at: Publisher Site | Google Scholar
C. Takatsuka, Y. Inoue, K. Matsuoka, and Y. Moriyasu, “3-Methyladenine inhibits autophagy in tobacco culture cells under sucrose starvation conditions,” Plant and Cell Physiology, vol. 45, no. 3, pp. 265–274, 2004.
View at: Publisher Site | Google Scholar
Y.-T. Wu, H.-L. Tan, G. Shui et al., “Dual role of 3-methyladenine in modulation of autophagy via different temporal patterns of inhibition on class I and III phosphoinositide 3-kinase,” Journal of Biological Chemistry, vol. 285, no. 14, pp. 10850–10861, 2010.
View at: Publisher Site | Google Scholar
M. F. Ethier and J. M. Madison, “LY294002, but not wortmannin, increases intracellular calcium and inhibits calcium transients in bovine and human airway smooth muscle cells,” Cell Calcium, vol. 32, no. 1, pp. 31–38, 2002.
View at: Publisher Site | Google Scholar

Copyright

Copyright © 2015 Raffaele Cursio et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

PDF Download Citation

Download other formats

Order printed copies

Views

3654

Downloads

1880

Citations