Outcomes and mechanisms of ischemic preconditioning in liver transplantation

Sheng Yan, Li-Ming Jin, Yuan-Xing Liu, Lin Zhou, Hai-Yang Xie and Shu-Sen Zheng

Hangzhou, China

Outcomes and mechanisms of ischemic preconditioning in liver transplantation

Sheng Yan, Li-Ming Jin, Yuan-Xing Liu, Lin Zhou, Hai-Yang Xie and Shu-Sen Zheng

Hangzhou, China

(Hepatobiliary Pancreat Dis Int 2010; 9: 346-354)

liver regeneration;ischemia/reperfusion injury;ischemic preconditioning;hepatectomy;liver transplantation

Introduction

Liver transplantation is so far the most effective therapeutic modality for end-stage liver diseases.Several non-immunological elements such as blood loss, ischemia/reperfusion (I/R) injury and regeneration capacity are associated with the outcome of liver transplantation. Hepatic in fl ow occlusion,termed as Pringle's maneuver,[1]represents an effective strategy to reduce blood loss and transfusion requirements in liver surgery, thus facilitating the technical development of liver transplantation.[2,3]However, this surgical strategy may contribute to hepatic I/R injury which impairs remnant liver/reducedsize-graft regeneration[4-7]as well as graft dysfunction after liver transplantation.[8-11]On the other hand, liver regeneration should be considered as a fundamental factor for partial liver transplantation including living donor liver transplantation (LDLT) and split liver transplantation. Ischemic preconditioning (IPC) as a practical strategy in theory not only protects the liver against I/R injury[12,13]but also enhances the capacity of liver regeneration.[14-17]IPC, which was described initially by Murry et al[18]in an animal model, refers to a brief period of I/R which can render an organ resistant to a more prolonged episode of ischemia, and it is generally evidenced with controversy.[4,13,19-24]Although investigators have attempted to explore the mechanism of IPC, the exact mechanism of IPC in liver transplantation is still not fully understood. In this article we reviewed a series of clinical and experimentalstudies in an attempt to investigate the protective effect and mechanism of IPC in liver transplantation.

Mechanisms of IPC

The protective mechanisms of IPC against hepatic I/R injury include alterations in energy metabolism,neutrophil accumulation, microcirculatory disturbances,liver regeneration, and formation of pro-in fl ammatory mediators.

Effect of IPC on energy metabolism

Mitochondria are the main energy production source for cells relevant to glutamate-/malate- or succinate oxidation.[25]Mitochondrial permeability transition leads to a rising permeability of the inner mitochondrial membrane, and consequently results in ATP depletion.[25]IPC might directly inhibits the negative effects of nonesteri fi ed fatty acids on β-oxidation or on the respiratory chain of mitochondria by protection of the mitochondrial permeability transition.[25,26]Among various protective mechanisms, the preservation of hepatic ATP contents plays an important role in mitigating I/R injury. A randomized controlled trial showed that IPC reduced metabolic cost of repairing more severe injuries.[27]IPC preserves hepatic energy metabolism via the downregulation of cellular ATP metabolism, thus enhancing nitric oxide (NO) synthesis and lowering arginase activity and lipid peroxidation.[28,29]Recent studies have shown that ATP-preserving effect of IPC is associated with increased expression of hepatic ATP synthase and its beta subunit.[25,30]

IPC and reactive oxygen species (ROSs)

ROSs deriving from activated Kupffer cells and neutrophils are one of the major detrimental elements in hepatic I/R injury. Xanthine dehydrogenase is converted to the oxygen radical-producing form xanthine oxidase(XOD) by I/R. Meanwhile, there is an accumulation of the substrate for XOD, xanthine. IPC is able to reduce the accumulation of xanthine and the conversion of xanthine dehydrogenase to XOD in liver grafts during cold ischemia. This endogenous protective mechanism has the capacity to block xanthine/XOD generation in liver grafts during cold ischemia.[31]Under reperfusion,XOD reacts with molecular oxygen to produce ROSs,which trigger a detrimental cascade, including cellular disintegration and microcirculatory dysfunction.Oxidative stress directly causes hepatocyte and/or sinusoidal endothelial cell (SEC) damage, whereas the soluble factors are largely responsible for the recruitment and activation of leukocytes. IPC can increase the hepatic tolerance to I/R injury by attenuating ROS production and oxidative stress.[32-34]By decreasing GSH depletion, IPC could be more effective in resisting ROS responses during hepatic ischemia.[35]A recent study suggested that IPC response is associated with the upregulation of mitochondrial superoxide dismutase and the decrease of ROS production.[36]

Effective role of IPC on hepatic microcirculation NO and endothelin

Hepatic microcirculation was modulated by vasoactive substances such as NO and endothelin, which balance a perfect intrahepatic microcirculation status via regulation of detailed vascular caliber and mediation of the sinusoidal perfusion.[37,38]Hepatic I/R imbalances the endogenous production of NO and endothelin,therefore distorts the sinusoidal lumen with consequently decreased leukocyte velocity and decreased perfusion.[9,39]The blockade of endogenous NO can aggravate microvascular and hepatocellular injury during the period of post-ischemic reperfusion.[40-42]IPC provides a better preservation of hepatic microcirculation,[43]with the effect similar to that induced by administering L-arginine and L-NAME, indicating that NO plays an important role in improving microcirculation.[37]After the blockade of NO, the remission of microcirculatory disturbance obliterated.[35,44]

SEC and adhesion molecules

The alteration of hepatic microcirculation is regarded as a critical target after hepatic I/R injury.[39,45]The underlying mechanisms of microcirculatory failure include narrowing of the sinusoid lumens due to the swelling of Kupffer cell, SEC[39]and hepatocyte.[37]Microcirculatory failure after I/R characterized by "nore fl ow" in sinusoids and "re fl ow-paradox" is associated with activation of Kupffer cell and release of in fl ammatory cytokines.[46]The over-expression of adhesion molecules(ICAM-1, VCAM-1, LFA, β2 integrin, E-selectin, etc) after I/R induces rolling of leukocytes along the endothelium of post-sinusoidal venules, which subsequently adhere to the SEC.[46,47]Kupffer cell and neutrophils are activated and release a series of in fl ammatory cytokines such as IL-1, IL-2, IL-4, IL-6 and TNF-α, which in turn activate leukocytes and increase the release of ROSs.[48-51]Studies have shown that the down-regulation of adhesion molecules can attenuate hepatic I/R injury.[51-55]

In 1999, Sawaya et al[56]found that IPC attenuated the status of rolling and adhesion of leukocyte, which decreases neutrophil in fi ltration in the liver. Indeed,the protection of IPC is closely related to the decrease of endothelial-leukocyte interaction.[57]Koti et al[58]found that the transient preconditioning episodes with hydrogen peroxide inhibited the expression of adhesion molecules and in fl ammatory factors by blockade of the NF-κB and mitogen-activated protein kinases(MAPK) signal transcription pathways.[59,60]Similarly,two in vitro studies of SEC suggested that the effect of IPC attributes to a decreased adhesion of neutrophils,secondary to a decreased production of endothelial adhesion molecules.[61,62]Although Peralta et al[63]suggested that neutrophil accumulation in the liver at 90 minutes of reperfusion after IPC did not induce the upregulation of ICAM-1, endothelial preconditioning may well explain the anti-adhesive effect of IPC.[64]

Mechanism of liver regeneration of IPC

Liver regeneration is a complex biological process,including numerous cellular components and mediators such as IL-6, TNF-α, signal transducer and activator of transcription (STAT)-3, stellate cells, and platelets.[65,66]Among these components and mediators, IL-6 and TNF-α are a sort of pleiotropic cytokine, which plays a central role in the process of in fl ammation and regeneration.[15,17,67,68]TNF-α promotes cell proliferation by inducing IL-6 production, and the regeneration is activated via the up-regulation of NF-κB,[67]while activating STAT-3.[68-70]STAT-3 is crucial for cell cycle progression in hepatocytes during liver regeneration.After STAT-3 and MAPK cascade are activated by the binding of cytokines like TNF-α and IL-6, the control of the intracellular signal transduction pathway is involved in liver regeneration. For instance, upon nuclear shuttling, STAT-3 binds to the promoter of immediate early genes and activates the MAPK pathway,like MAPK (p38) and c-Jun N-terminal kinase,[71-73]which in turn triggers the production of DNA synthesis proteins, like proliferating cell nuclear antigen (PCNA)protein.[74]The p38 directly regulates cell proliferation and differentiation, and is indirectly involved in the regulation of NF-κB-dependent transcriptional activity.[75,76]Thus, IPC inhibits the production of TNF-α at the early phase after reperfusion, but not IL-6 at the late phase of reperfusion in rats. Bedirli et al[17]suggested that IPC ameliorates hepatic I/R injury, and stimulates liver regeneration by a TNF-α/IL-6-dependent pathway as well. IPC improves the regeneration of small-for-size liver grafts, which involves in energy metabolism most likely by up-regulating mitochondrial superoxide dismutase and decreasing ROS production.[36,77]The facilitation of IPC for liver regeneration will be an option for the development of new strategies in LDLT.

Application of IPC in liver transplantation Whether is IPC a friendly strategy to LDLT?

LDLT as an established alternative to deceased donor liver transplantation (DDLT), has additional risk for the donor.[78,79]In almost all liver transplant centers donor hepatectomy has been performed in LDLT in the absence of hilar occlusion to avoid I/R injury.[80-85]A number of clinical trials, however, con fi rmed that in fl ow occlusion can be applied to living donor hepatectomy without graft injury.[86,87]Moreover transaction surface remains blood free, which decreases the risk to the donor in LDLT.[87]Thus in fl ow occlusion technique is used in a number of cases in which part of the graft can be completely ischemic during liver parenchymal dissection, and it has been con fi rmed that Pringle's technique does not elevate postoperative AST levels and can be used in donor hepatectomy. This technique makes hepatectomy more precisely and meticulously with least surgical injuries and anatomical complications.[86]In 2000, Clavien et al[88]initiated IPC strategy in clinical practice, indicating that IPC was promising in hepatectomy for preventing bleeding and lowering the risk of surgery in healthy donors. In fact,IPC not only prevents the liver from I/R injury but also decreases the intraoperative blood loss. Nuzzo et al[89]have evaluated the safety of IPC in a prolonged period of clamping in 42 consecutive patients with healthy liver for hepatectomy. The results indicated that IPC with Pringle's maneuver controls intraoperative bleeding. Thus IPC is considered effective to control bleeding and protect donors and grafts function during the procurement of LDLT. In fact many surgeons often delineate some lines of demarcation via clamping the entire hepatoduodenal ligament or the lobar in fl ow vessels for a brief period before liver resection, including LDLT. Fung[90]also support that this clamping invokes the same protective responses of IPC in liver surgery.

Increasingly successful hepatectomy documents using IPC strategy[21,88,91-94]also imply the potential bene fi ts of IPC to the harvesting from the living donor. Arai et al[95]suggested that it is feasible to precondition liver tissue before liver donation in LDLT.Most recently, Chouker et al[93]reported that IPC offers a better intraoperative hemodynamic stability by lowering the need for catecholamine. Furthermore,the simple strategy offers further advantages and brings preconditioning closer to organ harvesting.[13]Therefore, IPC as a modi fi ed Pringle's maneuver should not be hesitatedly used by surgeons during LDLT, at least it should be conducted in a series of clinical trials.However, evidence is insuf fi cient for the establishment of a protective theory of IPC against donor and graft injury during LDLT (Tables 1-3).

IPC and partial liver transplantation

The capacity of regeneration after partial liver transplantation is an elementary contributor to the clinical outcome.[96,97]The effect of IPC on liver cell cycle is associated with the production of IL-6.[67,68]Matsumoto et al[15]found that the liver regeneration mechanism of IPC against total hepatic I/R injury was induced by the modulation of the IL-6/STAT-3 signaling pathway.

The adverse effect on liver regeneration is thought to be induced by drastic reduction in the hepatic microvascular bed, leading to excessive portal perfusion injury in a small-for-size liver graft.[98-101]As mentioned, IPC is potentially able to improve liver regeneration after LDLT. Franco-Gou et al[6]suggested that IPC promoted liver regeneration by increasing PCNA indices and hepatocyte growth factor levels. In addition, IPC decreases liver injury after reperfusion and improves graft survival after whole and partial liver transplantation.[95,102]This may be a bene fi cial IPC effect on reduced-size liver transplantation via blocking mitochondrial depolarization. Although a clinical observation revealed that IPC was likely to be ineffective in case of hepatic volume loss above 50%,[103]most experimental studies claimed that IPC can improve hepatic proliferation if hepatectomy is not more than 70%.[17,99,104]In addition, other supplementary strategies plus IPC may induce liver regeneration with a graft size of 30% or less in LDLT.[104]Arai et al[77]indicated that IPC enhances the capacity of liver regeneration after 70% hepatectomy.

Besides, the duration of liver ischemic injury may impair its regeneration. Yamada et al[105]foundthat IPC with 40 minutes ischemia had a better regenerative capacity than that with 2-hour ischemia.Another study also showed that IPC maintains liver regeneration capacity by enhancing survival signals but fails to prevent I/R injury in the liver subjected to warm ischemia for more than 60 minutes.[16]However,unilateral IPC prior to graft procurement does not produce any bene fi cial clinical effect or trigger any signi fi cant protective effect on tissue (Tables 1-3).[106]

Table 1. Liver regeneration of IPC after partial hepatectomy in rodents

Table 2. Clinical studies of IPC in hepatectomy

Table 3. Prospective clinical trials of IPC in LDLT and DDLT

IPC and DDLT

To our knowledge, Azoulay et al[115]fi rst demonstrated the protective effect of IPC in DDLT. Although various basic and clinical studies of IPC were performed, the role of IPC or its protective effect in DDLT remains controversial.[8,119]IPC has the potential to ameliorate graft injury and decrease morbidity after liver transplantation. However, Koneru et al[114]observed that deceased donor liver with 5-minute I/R does not induce a response to IPC, showing two possibilities:5-minute preconditioning interval is too short to induce protection; and protective response is too slender. Two years later, however, they found that a trend towards fewer moderate/severe rejections is related to IPC via upregulating the expression of IL-10 after DDLT.[117]Similarly, Jassem et al[116,120]reported that IPC confers protection against in fl ammatory responses, which are associated with the impairment of cadaveric liver graft function in a long period.

Although IPC causes an early decreased allograft function, a previous clinical trial[115]indicated that IPC provides a better tolerance to ischemia. Subsequently,Cescon et al[121]found that 10-minute IPC has a signi fi cant bene fi cial effect on reduction of ALT in a deceased donor allograft, but it has no clinical bene fi t.A recent randomized clinical trial showed that IPC decreases postoperative liver enzymes, improves signi fi cantly biochemical markers of liver function, and reduces the probability of reoperation (Table 3).[22]

Funding: This study was supported by grants from the National Key Technology R&D Program in the Eleventh Five-Year Plan of China (No. 2008BAI60B02 and 2008BAI60B06), and the National Natural Science Foundation of China (No. 30700769).

Ethical approval: Not needed.

Contributors: YS wrote the fi rst draft of this paper. All authors contributed to the intellectual context and approved the fi nal version. ZSS is the guarantor.

Competing interest: No bene fi ts in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

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BACKGROUND: Liver transplantation is so far the most effective therapeutic modality for end-stage liver diseases,but ischemia/reperfusion (I/R) injury represents a critical barrier to liver transplantation. Primary graft dysfunction and small-for-size syndrome are closely associated with I/R injury. Ischemic preconditioning (IPC) is de fi ned as a brief period of liver ischemia followed by reperfusion, and has demonstrated protections against a prolonged I/R injury and improved the capacity of regeneration. The article aimed to review IPC literatures for the understanding of the effects of IPC on I/R injury involving in the procurement of donor liver and protective mechanisms.

DATA SOURCES: A literature search of MEDLINE and Web of Science databases using "liver transplantation", "liver regeneration", "hepatectomy", "ischemia/reperfusion" and"ischemic preconditioning" was performed, and then a large amount of related data was collected.

RESULTS: The literature search provided a huge amount of evidence for the protective effects of IPC on I/R injury in liver transplantation, including reduction of blood loss in hepatectomy, intraoperative hemodynamic stability and its signi fi cant role in liver regeneration. The mechanism involves in balancing in fl ammatory cytokines, enhancing energy status and mitigating microcirculatory disturbance.CONCLUSION: IPC plays an essential role in hepatectomy before and after harvest of living donor liver and implantation of liver graft.

Author Af fi liations: Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, First Af fi liated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China (Yan S, Jin LM,Liu YX, Zhou L, Xie HY and Zheng SS)

Shu-Sen Zheng, MD, PhD, FACS, Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, First Af fi liated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China (Tel: 86-571-87236567; Fax: 86-571-87236884; Email:shusenzheng@zju.edu.cn)

? 2010, Hepatobiliary Pancreat Dis Int. All rights reserved.

October 8, 2009

Accepted after revision April 23, 2010