• ISSN 16748301
  • CN 32-1810/R
Volume 33 Issue 4
Jul.  2019
Article Contents


Hepatic ischemia-reperfusion injury in liver transplant setting: mechanisms and protective strategies

  • Corresponding author: Daqing Ma, d.ma@imperial.ac.uk
  • Received Date: 2018-09-12
    Accepted Date: 2018-10-10
  • Hepatic ischemia-reperfusion injury is a major cause of liver transplant failure, and is of increasing significance due to increased use of expanded criteria livers for transplantation. This review summarizes the mechanisms and protective strategies for hepatic ischemia-reperfusion injury in the context of liver transplantation. Pharmacological therapies, the use of pre-and post-conditioning and machine perfusion are discussed as protective strategies. The use of machine perfusion offers significant potential in the reconditioning of liver grafts and the prevention of hepatic ischemia-reperfusion injury, and is an exciting and active area of research, which needs more study clinically.
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  • [1] Ikeda T, Yanaga K, Kishikawa K, et al. Ischemic injury in liver transplantation: difference in injury sites between warm and cold ischemia in rats[J]. Hepatology, 1992, 16(2): 454–461. doi: 10.1002/hep.1840160226
    [2] Jaeschke H. Reperfusion injury after warm ischemia or cold storage of the liver: role of apoptotic cell death[J]. Transplant Proc, 2002, 34(7): 2656–2658. doi: 10.1016/S0041-1345(02)03464-4
    [3] Huet PM, Nagaoka MR, Desbiens G, et al. Sinusoidal endothelial cell and hepatocyte death following cold ischemia-warm reperfusion of the rat liver[J]. Hepatology, 2004, 39(4): 1110–1119. doi: 10.1002/hep.20157
    [4] Kupiec-Weglinski JW, Busuttil RW. Ischemia and reperfusion injury in liver transplantation[J]. Transplant Proc, 2005, 37(4): 1653–1656. doi: 10.1016/j.transproceed.2005.03.134
    [5] Zhai Y, Busuttil RW, Kupiec-Weglinski JW. Liver ischemia and reperfusion injury: new insights into mechanisms of innate-adaptive immune-mediated tissue inflammation[J]. Am J Transplant, 2011, 11(8): 1563–1569. doi: 10.1111/ajt.2011.11.issue-8
    [6] Pine JK, Aldouri A, Young AL, et al. Liver transplantation following donation after cardiac death: an analysis using matched pairs[J]. Liver Transpl, 2009, 15(9): 1072–1082. doi: 10.1002/lt.v15:9
    [7] Howard TK, Klintmalm GBG, Cofer JB, et al. The influence of preservation injury on rejection in the hepatic transplant recipient[J]. Transplantation, 1990, 49(1): 103–107. doi: 10.1097/00007890-199001000-00023
    [8] Fellström B, Aküyrek LM, Backman U, et al. Postischemic reperfusion injury and allograft arteriosclerosis[J]. Transplant Proc, 1998, 30(8): 4278–4280. doi: 10.1016/S0041-1345(98)01412-2
    [9] Guo WA. The search for a magic bullet to fight multiple organ failure secondary to ischemia/reperfusion injury and abdominal compartment syndrome[J]. J Surg Res, 2013, 184(2): 792–793. doi: 10.1016/j.jss.2012.06.024
    [10] Wertheim JA, Petrowsky H, Saab S, et al. Major challenges limiting liver transplantation in the United States[J]. Am J Transplant, 2011, 11(9): 1773–1784. doi: 10.1111/j.1600-6143.2011.03587.x
    [11] Neuberger J. Liver transplantation in the United Kingdom[J]. Liver Transpl, 2016, 22(8): 1129–1135. doi: 10.1002/lt.v22.8
    [12] NHS Blood and Transplant. Annual activity report[EB/OL]. [2017-02-07]. www.odt.nhs.uk.
    [13] Singal AK, Guturu P, Hmoud B, et al. Evolving frequency and outcomes of liver transplantation based on etiology of liver disease[J]. Transplantation, 2013, 95(5): 755–760. doi: 10.1097/TP.0b013e31827afb3a
    [14] Casillas-Ramírez A, Mosbah IB, Ramalho F, et al. Past and future approaches to ischemia-reperfusion lesion associated with liver transplantation[J]. Life Sci, 2006, 79(20): 1881–1894. doi: 10.1016/j.lfs.2006.06.024
    [15] Fan CG, Zwacka RM, Engelhardt JF. Therapeutic approaches for ischemia/reperfusion injury in the liver[J]. J Mol Med (Berl), 1999, 77(8): 577–592. doi: 10.1007/s001099900029
    [16] Zwacka RM, Zhou WH, Zhang YL, et al. Redox gene therapy for ischemia/reperfusion injury of the liver reduces AP1 and NF-κB activation[J]. Nat Med, 1998, 4(6): 698–704. doi: 10.1038/nm0698-698
    [17] Teoh NC, Farrell GC. Hepatic ischemia reperfusion injury: pathogenic mechanisms and basis for hepatoprotection[J]. J Gastroenterol Hepatol, 2003, 18(8): 891–902. doi: 10.1046/j.1440-1746.2003.03056.x
    [18] Mavier P, Preaux AM, Guigui B, et al. In vitro toxicity of polymorphonuclear neutrophils to rat hepatocytes: evidence for a proteinase-mediated mechanism[J]. Hepatology, 1988, 8(2): 254–258. doi: 10.1002/hep.1840080211
    [19] Li XK, Matin AF, Suzuki H, et al. Effect of protease inhibitor on ischemia/reperfusion injury of the rat liver[J]. Transplantation, 1993, 56(6): 1331–1336. doi: 10.1097/00007890-199312000-00008
    [20] Nastos C, Kalimeris K, Papoutsidakis N, et al. Global consequences of liver ischemia/reperfusion injury[J]. Oxid Med Cell Longev, 2014, 2014: 906965.
    [21] Selzner M, Selzner N, Jochum W, et al. Increased ischemic injury in old mouse liver: an ATP-dependent mechanism[J]. Liver Transpl, 2007, 13(3): 382–390. doi: 10.1002/lt.21100
    [22] Wang D, Dou K, Song Z, et al. The Na(+)/H(+) exchange inhibitor: a new therapeutic approach for hepatic ischemia injury in rats[J]. Transplant Proc, 2003, 35(8): 3134–3135. doi: 10.1016/j.transproceed.2003.10.021
    [23] Carini R, De Cesaris MG, Splendore R, et al. Alterations of Na+ homeostasis in hepatocyte reoxygenation injury[J]. Biochim Biophys Acta, 2000, 1500(3): 297–305. doi: 10.1016/S0925-4439(99)00114-3
    [24] Nishimura Y, Romer LH, Lemasters JJ. Mitochondrial dysfunction and cytoskeletal disruption during chemical hypoxia to cultured rat hepatic sinusoidal endothelial cells: the pH paradox and cytoprotection by glucose, acidotic pH, and glycine[J]. Hepatology, 1998, 27(4): 1039–1049. doi: 10.1002/hep.510270420
    [25] Vairetti M, Richelmi P, Bertè F, et al. Role of pH in protection by low sodium against hypoxic injury in isolated perfused rat livers[J]. J Hepatol, 2006, 44(5): 894–901. doi: 10.1016/j.jhep.2005.08.007
    [26] Gores GJ, Nieminen AL, Wray BE, et al. Intracellular pH during " chemical hypoxia” in cultured rat hepatocytes. Protection by intracellular acidosis against the onset of cell death[J]. J Clin Invest, 1989, 83(2): 386–396. doi: 10.1172/JCI113896
    [27] Jiang N, Zhang ZM, Liu L, et al. Effects of Ca2+ channel blockers on store-operated Ca2+ channel currents of Kupffer cells after hepatic ischemia/reperfusion injury in rats[J]. World J Gastroenterol, 2006, 12(29): 4694–4698. doi: 10.3748/wjg.v12.i29.4694
    [28] Barritt GJ, Chen JL, Rychkov GY. Ca2+-permeable channels in the hepatocyte plasma membrane and their roles in hepatocyte physiology[J]. Biochim Biophys Acta, 2008, 1783(5): 651–672. doi: 10.1016/j.bbamcr.2008.01.016
    [29] Wang HG, Pathan N, Ethell IM, et al. Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD[J]. Science, 1999, 284(5412): 339–343. doi: 10.1126/science.284.5412.339
    [30] Anderson CD, Pierce J, Nicoud I, et al. Modulation of mitochondrial calcium management attenuates hepatic warm ischemia-reperfusion injury[J]. Liver Transpl, 2005, 11(6): 663–668. doi: 10.1002/lt.20407
    [31] Jaeschke H, Lemasters JJ. Apoptosis versus oncotic necrosis in hepatic ischemia/reperfusion injury[J]. Gastroenterology, 2003, 125(4): 1246–1257. doi: 10.1016/S0016-5085(03)01209-5
    [32] Nauta RJ, Tsimoyiannis E, Uribe M, et al. The role of calcium ions and calcium channel entry blockers in experimental ischemia-reperfusion-induced liver injury[J]. Ann Surg, 1991, 213(2): 137–142. doi: 10.1097/00000658-199102000-00008
    [33] Hataji K, Watanabe T, Oowada S, et al. Effects of a calcium-channel blocker (CV159) on hepatic ischemia/reperfusion injury in rats: evaluation with selective NO/pO2 electrodes and an electron paramagnetic resonance spin-trapping method[J]. Biol Pharm Bull, 2010, 33(1): 77–83. doi: 10.1248/bpb.33.77
    [34] Nicoud IB, Knox CD, Jones CM, et al. 2-APB protects against liver ischemia-reperfusion injury by reducing cellular and mitochondrial calcium uptake[J]. Am J Physiol Gastrointest Liver Physiol, 2007, 293(3): G623–G630. doi: 10.1152/ajpgi.00521.2006
    [35] Pronobesh C, Dagagi AV, Pallab C, et al. Protective role of the calcium channel blocker amlodipine against mitochondrial injury in ischemia and reperfusion injury of rat liver[J]. Acta Pharm, 2008, 58(4): 421–428.
    [36] Abu-Amara M, Yang SY, Tapuria N, et al. Liver ischemia/reperfusion injury: processes in inflammatory networks—a review[J]. Liver Transpl, 2010, 16(9): 1016–1032. doi: 10.1002/lt.22117
    [37] Elmore SP, Qian T, Grissom SF, et al. The mitochondrial permeability transition initiates autophagy in rat hepatocytes[J]. FASEB J, 2001, 15(12): 2286–2287. doi: 10.1096/fj.01-0206fje
    [38] Kim I, Rodriguez-Enriquez S, Lemasters JJ. Selective degradation of mitochondria by mitophagy[J]. Arch Biochem Biophys, 2007, 462(2): 245–253. doi: 10.1016/j.abb.2007.03.034
    [39] Zhao KS, Zhao GM, Wu DL, et al. Cell-permeable peptide antioxidants targeted to inner mitochondrial membrane inhibit mitochondrial swelling, oxidative cell death, and reperfusion injury[J]. J Biol Chem, 2004, 279(33): 34682–34690. doi: 10.1074/jbc.M402999200
    [40] Kim JS, Qian T, Lemasters JJ. Mitochondrial permeability transition in the switch from necrotic to apoptotic cell death in ischemic rat hepatocytes[J]. Gastroenterology, 2003, 124(2): 494–503. doi: 10.1053/gast.2003.50059
    [41] Sastre J, Serviddio G, Pereda J, et al. Mitochondrial function in liver disease[J]. Front Biosci, 2007, 12: 1200–1209. doi: 10.2741/2138
    [42] Videla LA. Cytoprotective and suicidal signaling in oxidative stress[J]. Biol Res, 2010, 43(3): 363–369.
    [43] Hines IN, Hoffman JM, Scheerens H, et al. Regulation of postischemic liver injury following different durations of ischemia[J]. Am J Physiol Gastrointest Liver Physiol, 2003, 284(3): G536–G545. doi: 10.1152/ajpgi.00400.2002
    [44] Jaeschke H. Mechanisms of Liver Injury. II. Mechanisms of neutrophil-induced liver cell injury during hepatic ischemia-reperfusion and other acute inflammatory conditions[J]. Am J Physiol Gastrointest Liver Physiol, 2006, 290(6): G1083–G1088. doi: 10.1152/ajpgi.00568.2005
    [45] Spencer NY, Zhou WH, Li Q, et al. Hepatocytes produce TNF-α following hypoxia-reoxygenation and liver ischemia-reperfusion in a NADPH oxidase- and c-Src-dependent manner[J]. Am J Physiol Gastrointest Liver Physiol, 2013, 305(1): G84–G94. doi: 10.1152/ajpgi.00430.2012
    [46] Reiniers MJ, van Golen RF, van Gulik TM, et al. Reactive oxygen and nitrogen species in steatotic hepatocytes: a molecular perspective on the pathophysiology of ischemia-reperfusion injury in the fatty liver[J]. Antioxid Redox Signal, 2014, 21(7): 1119–1142. doi: 10.1089/ars.2013.5486
    [47] Pardini RS. Toxicity of oxygen from naturally occurring redox-active pro-oxidants[J]. Arch Insect Biochem Physiol, 1995, 29(2): 101–118. doi: 10.1002/arch.940290203
    [48] Jaeschke H. Reactive oxygen and mechanisms of inflammatory liver injury: present concepts[J]. J Gastroenterol Hepatol, 2011, 26(S1): 173–179.
    [49] Guicciardi ME, Malhi H, Mott JL, et al. Apoptosis and necrosis in the liver[J]. Compr Physiol, 2013, 3(2): 977–1010.
    [50] Rauen U, Polzar B, Stephan H, et al. Cold-induced apoptosis in cultured hepatocytes and liver endothelial cells: mediation by reactive oxygen species[J]. FASEB J, 1999, 13(1): 155–168. doi: 10.1096/fasebj.13.1.155
    [51] Kawada N, Tran-Thi TA, Klein H, et al. The contraction of hepatic stellate (Ito) cells stimulated with vasoactive substances: Possible involvement of endothelin 1 and nitric oxide in the regulation of the sinusoidal tonus[J]. Eur J Biochem, 1993, 213(2): 815–823. doi: 10.1111/ejb.1993.213.issue-2
    [52] Kawamura E, Yamanaka N, Okamoto E, et al. Response of plasma and tissue endothelin-1 to liver ischemia and its implication in ischemia-reperfusion injury[J]. Hepatology, 1995, 21(4): 1138–1143. doi: 10.1016/0270-9139(95)90266-X
    [53] Lefer AM, Lefer DJ. Nitric oxide. II. Nitric oxide protects in intestinal inflammation[J]. Am J Physiol, 1999, 276(3 Pt 1): G572–G575.
    [54] Hamada T, Duarte S, Tsuchihashi S, et al. Inducible nitric oxide synthase deficiency impairs matrix metalloproteinase-9 activity and disrupts leukocyte migration in hepatic ischemia/reperfusion injury[J]. Am J Pathol, 2009, 174(6): 2265–2277. doi: 10.2353/ajpath.2009.080872
    [55] Abu-Amara M, Yang SY, Seifalian A, et al. The nitric oxide pathway-evidence and mechanisms for protection against liver ischaemia reperfusion injury[J]. Liver Int, 2012, 32(4): 531–543. doi: 10.1111/liv.2012.32.issue-4
    [56] Chen C, Lee WH, Zhong LW, et al. Regulatory T cells can mediate their function through the stimulation of APCs to produce immunosuppressive nitric oxide[J]. J Immunol, 2006, 176(6): 3449–3460. doi: 10.4049/jimmunol.176.6.3449
    [57] Phillips L, Toledo AH, Lopez-Neblina F, et al. Nitric oxide mechanism of protection in ischemia and reperfusion injury[J]. J Invest Surg, 2009, 22(1): 46–55. doi: 10.1080/08941930802709470
    [58] Lang JD Jr, Teng XJ, Chumley P, et al. Inhaled NO accelerates restoration of liver function in adults following orthotopic liver transplantation[J]. J Clin Invest, 2007, 117(9): 2583–2591. doi: 10.1172/JCI31892
    [59] Duranski MR, Greer JJM, Dejam A, et al. Cytoprotective effects of nitrite during in vivo ischemia-reperfusion of the heart and liver[J]. J Clin Invest, 2005, 115(5): 1232–1240. doi: 10.1172/JCI22493
    [60] Li W, Meng ZH, Liu YL, et al. The hepatoprotective effect of sodium nitrite on cold ischemia-reperfusion injury[J]. J Transplant, 2012, 2012: 635179.
    [61] Shiratori Y, Kiriyama H, Fukushi Y, et al. Modulation of ischemia-reperfusion-induced hepatic injury by Kupffer cells[J]. Dig Dis Sci, 1994, 39(6): 1265–1272. doi: 10.1007/BF02093792
    [62] Jaeschke H, Bautista AP, Spolarics Z, et al. Superoxide generation by neutrophils and Kupffer cells during in vivo reperfusion after hepatic ischemia in rats[J]. J Leukoc Biol, 1992, 52(4): 377–382. doi: 10.1002/jlb.1992.52.issue-4
    [63] Fondevila C, Shen XD, Tsuchihashi S, et al. The membrane attack complex (C5b-9) in liver cold ischemia and reperfusion injury[J]. Liver Transpl, 2008, 14(8): 1133–1141. doi: 10.1002/lt.v14:8
    [64] Brock RW, Nie RG, Harris KA, et al. Kupffer cell-initiated remote hepatic injury following bilateral hindlimb ischemia is complement dependent[J]. Am J Physiol Gastrointest Liver Physiol, 2001, 280(2): G279–G284. doi: 10.1152/ajpgi.2001.280.2.G279
    [65] Llacuna L, Marí M, Lluis JM, et al. Reactive oxygen species mediate liver injury through parenchymal nuclear factor-κB inactivation in prolonged ischemia/reperfusion[J]. Am J Pathol, 2009, 174(5): 1776–1785. doi: 10.2353/ajpath.2009.080857
    [66] Selzner N, Selzner M, Odermatt B, et al. ICAM-1 triggers liver regeneration through leukocyte recruitment and Kupffer cell-dependent release of TNF-α/IL-6 in mice[J]. Gastroenterology, 2003, 124(3): 692–700. doi: 10.1053/gast.2003.50098
    [67] Boury NM, Czuprynski CJ. Listeria monocytogenes infection increases neutrophil adhesion and damage to a murine hepatocyte cell line in vitro[J]. Immunol Lett, 1995, 46(1–2): 111–116. doi: 10.1016/0165-2478(95)00027-3
    [68] Hanschen M, Zahler S, Krombach F, et al. Reciprocal activation between CD4+ T cells and Kupffer cells during hepatic ischemia-reperfusion[J]. Transplantation, 2008, 86(5): 710–718. doi: 10.1097/TP.0b013e3181821aa7
    [69] Nishimura Y, Takei Y, Kawano S, et al. The F(ab’)2 fragment of an anti-ICAM-1 monoclonal antibody attenuates liver injury after orthotopic liver transplantation[J]. Transplantation, 1996, 61(1): 99–104. doi: 10.1097/00007890-199601150-00020
    [70] Fong Y, Moldawer LL, Shires GT, et al. The biologic characteristics of cytokines and their implication in surgical injury[J]. Surg Gynecol Obstet, 1990, 170(4): 363–378.
    [71] Leifeld L, Cheng S, Ramakers J, et al. Imbalanced intrahepatic expression of interleukin 12, interferon gamma, and interleukin 10 in fulminant hepatitis B[J]. Hepatology, 2002, 36(4 Pt 1): 1001–1008.
    [72] Lentsch AB, Yoshidome H, Kato A, et al. Requirement for interleukin-12 in the pathogenesis of warm hepatic ischemia/reperfusion injury in mice[J]. Hepatology, 1999, 30(6): 1448–1453. doi: 10.1002/hep.510300615
    [73] Husted TL, Blanchard J, Schuster R, et al. Potential role for IL-23 in hepatic ischemia/reperfusion injury[J]. Inflamm Res, 2006, 55(5): 177–178. doi: 10.1007/s00011-006-0073-1
    [74] Colletti LM, Remick DG, Burtch GD, et al. Role of tumor necrosis factor-alpha in the pathophysiologic alterations after hepatic ischemia/reperfusion injury in the rat[J]. J Clin Invest, 1990, 85(6): 1936–1943. doi: 10.1172/JCI114656
    [75] Colletti LM, Kunkel SL, Walz A, et al. Chemokine expression during hepatic ischemia/reperfusion-induced lung injury in the rat. The role of epithelial neutrophil activating protein[J]. J Clin Invest, 1995, 95(1): 134–141. doi: 10.1172/JCI117630
    [76] Colletti LM, Cortis A, Lukacs N, et al. Tumor necrosis factor up-regulates intercellular adhesion molecule 1, which is important in the neutrophil-dependent lung and liver injury associated with hepatic ischemia and reperfusion in the rat[J]. Shock, 1998, 10(3): 182–191. doi: 10.1097/00024382-199809000-00006
    [77] Shito M, Wakabayashi G, Ueda M, et al. Interleukin 1 receptor blockade reduces tumor necrosis factor production, tissue injury, and mortality after hepatic ischemia-reperfusion in the rat[J]. Transplantation, 1997, 63(1): 143–148. doi: 10.1097/00007890-199701150-00026
    [78] Djeu JY, Matsushima K, Oppenheim JJ, et al. Functional activation of human neutrophils by recombinant monocyte-derived neutrophil chemotactic factor/IL-8[J]. J Immunol, 1990, 144(6): 2205–2210.
    [79] Lentsch AB, Yoshidome H, Cheadle WG, et al. Chemokine involvement in hepatic ischemia/reperfusion injury in mice: roles for macrophage inflammatory protein-2 and Kupffer cells[J]. Hepatology, 1998, 27(2): 507–512. doi: 10.1002/hep.510270226
    [80] Ke BB, Shen XD, Lassman CR, et al. Cytoprotective and antiapoptotic effects of IL-13 in hepatic cold ischemia/reperfusion injury are heme oxygenase-1 dependent[J]. Am J Transplant, 2003, 3(9): 1076–1082. doi: 10.1034/j.1600-6143.2003.00147.x
    [81] Reiter RJ, Paredes SD, Manchester LC, et al. Reducing oxidative/nitrosative stress: a newly-discovered genre for melatonin[J]. Crit Rev Biochem Mol Biol, 2009, 44(4): 175–200. doi: 10.1080/10409230903044914
    [82] López-Burillo S, Tan DX, Rodriguez-Gallego V, et al. Melatonin and its derivatives cyclic 3-hydroxymelatonin, N1-acetyl-N2-formyl-5-methoxykynuramine and 6-methoxymelatonin reduce oxidative DNA damage induced by Fenton reagents[J]. J Pineal Res, 2003, 34(3): 178–184. doi: 10.1111/jpi.2003.34.issue-3
    [83] Barlow-Walden LR, Reiter RJ, Abe M, et al. Melatonin stimulates brain glutathione peroxidase activity[J]. Neurochem Int, 1995, 26(5): 497–502. doi: 10.1016/0197-0186(94)00154-M
    [84] Reiter RJ, Tan DX, Osuna C, et al. Actions of melatonin in the reduction of oxidative stress: a review[J]. J Biomed Sci, 2000, 7(6): 444–458. doi: 10.1007/BF02253360
    [85] Okatani Y, Wakatsuki A, Reiter RJ, et al. Protective effect of melatonin against mitochondrial injury induced by ischemia and reperfusion of rat liver[J]. Eur J Pharmacol, 2003, 469(1–3): 145–152. doi: 10.1016/S0014-2999(03)01643-1
    [86] Kireev R, Bitoun S, Cuesta S, et al. Melatonin treatment protects liver of Zucker rats after ischemia/reperfusion by diminishing oxidative stress and apoptosis[J]. Eur J Pharmacol, 2013, 701(1–3): 185–193. doi: 10.1016/j.ejphar.2012.11.038
    [87] Vairetti M, Ferrigno A, Bertone R, et al. Exogenous melatonin enhances bile flow and ATP levels after cold storage and reperfusion in rat liver: implications for liver transplantation[J]. J Pineal Res, 2005, 38(4): 223–230. doi: 10.1111/jpi.2005.38.issue-4
    [88] De Deken J, Rex S, Monbaliu D, et al. The efficacy of noble gases in the attenuation of ischemia reperfusion injury: a systematic review and meta-analyses[J]. Crit Care Med, 2016, 44(9): e886–e896. doi: 10.1097/CCM.0000000000001717
    [89] Wilke HJ, Moench C, Lotz G, et al. Xenon anesthesia for liver transplant surgery: a report of four cases[J]. Transplant Proc, 2011, 43(7): 2683–2686. doi: 10.1016/j.transproceed.2011.06.029
    [90] Thies JC, Teklote J, Clauer U, et al. The efficacy of N-acetylcysteine as a hepatoprotective agent in liver transplantation[J]. Transpl Int, 1998, 11(S1): S390–S392. doi: 10.1111/j.1432-2277.1998.tb01164.x
    [91] Weigand MA, Plachky J, Thies JC, et al. N-acetylcysteine attenuates the increase in α-glutathione S-transferase and circulating ICAM-1 and VCAM-1 after reperfusion in humans undergoing liver transplantation[J]. Transplantation, 2001, 72(4): 694–698. doi: 10.1097/00007890-200108270-00023
    [92] Bucuvalas JC, Ryckman FC, Krug S, et al. Effect of treatment with prostaglandin E1 and N-acetylcysteine on pediatric liver transplant recipients: a single-center study[J]. Pediatr Transplant, 2001, 5(4): 274–278. doi: 10.1034/j.1399-3046.2001.005004274.x
    [93] Bromley PN, Cottam SJ, Hilmi I, et al. Effects of intraoperative N-acetylcysteine in orthotopic liver transplantation[J]. Br J Anaesth, 1995, 75(3): 352–354. doi: 10.1093/bja/75.3.352
    [94] Steib A, Freys G, Collin F, et al. Does N-acetylcysteine improve hemodynamics and graft function in liver transplantation?[J]. Liver Transpl Surg, 1998, 4(2): 152–157. doi: 10.1002/(ISSN)1527-6473a
    [95] Tsuchihashi SI, Fondevila C, Shaw GD, et al. Molecular characterization of rat leukocyte P-selectin glycoprotein ligand-1 and effect of its blockade: protection from ischemia-reperfusion injury in liver transplantation[J]. J Immunol, 2006, 176(1): 616–624. doi: 10.4049/jimmunol.176.1.616
    [96] Dulkanchainun TS, Goss JA, Imagawa DK, et al. Reduction of hepatic ischemia/reperfusion injury by a soluble P-selectin glycoprotein ligand-1[J]. Ann Surg, 1998, 227(6): 832–840. doi: 10.1097/00000658-199806000-00006
    [97] Amersi F, Farmer DG, Shaw GD, et al. P-selectin glycoprotein ligand-1 (rPSGL-Ig)-mediated blockade of CD62 selectin molecules protects rat steatotic liver grafts from ischemia/reperfusion injury[J]. Am J Transplant, 2002, 2(7): 600–608. doi: 10.1034/j.1600-6143.2002.20704.x
    [98] Busuttil RW, Lipshutz GS, Kupiec-Weglinski JW, et al. rPSGL-Ig for improvement of early liver allograft function: a double-blind, placebo-controlled, single-center phase II study[J]. Am J Transplant, 2011, 11(4): 786–797. doi: 10.1111/j.1600-6143.2011.03441.x
    [99] Valentino KL, Gutierrez M, Sanchez R, et al. First clinical trial of a novel caspase inhibitor: anti-apoptotic caspase inhibitor, IDN-6556, improves liver enzymes[J]. Int J Clin Pharmacol Ther, 2003, 41(10): 441–449. doi: 10.5414/CPP41441
    [100] Linton SD, Aja T, Armstrong RA, et al. First-in-class pan caspase inhibitor developed for the treatment of liver disease[J]. J Med Chem, 2005, 48(22): 6779–6782. doi: 10.1021/jm050307e
    [101] Baskin-Bey ES, Washburn K, Feng S, et al. Clinical trial of the pan-caspase inhibitor, IDN-6556, in human liver preservation injury[J]. Am J Transplant, 2007, 7(1): 218–225. doi: 10.1111/ajt.2007.7.issue-1
    [102] Song G, Ouyang GL, Bao SD. The activation of Akt/PKB signaling pathway and cell survival[J]. J Cell Mol Med, 2005, 9(1): 59–71. doi: 10.1111/jcmm.2005.9.issue-1
    [103] Covington SM, Bauler LD, Toledo-Pereyra LH. Akt: a therapeutic target in hepatic ischemia-reperfusion injury[J]. J Invest Surg, 2017, 30(1): 47–55. doi: 10.1080/08941939.2016.1206999
    [104] Koh PO. Melatonin prevents hepatic injury-induced decrease in Akt downstream targets phosphorylations[J]. J Pineal Res, 2011, 51(2): 214–219. doi: 10.1111/j.1600-079X.2011.00879.x
    [105] Bertoldo MJ, Faure M, Dupont J, et al. AMPK: a master energy regulator for gonadal function[J]. Front Neurosci, 2015, 9: 235.
    [106] Peralta C, Bartrons R, Serafin A, et al. Adenosine monophosphate-activated protein kinase mediates the protective effects of ischemic preconditioning on hepatic ischemia-reperfusion injury in the rat[J]. Hepatology, 2001, 34(6): 1164–1173. doi: 10.1053/jhep.2001.29197
    [107] Ding WX, Zhang Q, Dong YB, et al. Adiponectin protects the rats liver against chronic intermittent hypoxia induced injury through AMP-activated protein kinase pathway[J]. Sci Rep, 2016, 6: 34151. doi: 10.1038/srep34151
    [108] Zhang CZ, Liao Y, Li Q, et al. Recombinant adiponectin ameliorates liver ischemia reperfusion injury via activating the AMPK/eNOS pathway[J]. PLoS One, 2013, 8(6): e66382. doi: 10.1371/journal.pone.0066382
    [109] Lehrke M, Lazar MA. The many faces of PPARγ[J]. Cell, 2005, 123(6): 993–999. doi: 10.1016/j.cell.2005.11.026
    [110] Marion-Letellier R, Savoye G, Ghosh S. Fatty acids, eicosanoids and PPAR gamma[J]. Eur J Pharmacol, 2016, 785: 44–49. doi: 10.1016/j.ejphar.2015.11.004
    [111] Zhou YL, Jia S, Wang CJ, et al. FAM3A is a target gene of peroxisome proliferator-activated receptor gamma[J]. Biochim Biophys Acta, 2013, 1830(8): 4160–4170. doi: 10.1016/j.bbagen.2013.03.029
    [112] Yang WL, Chen J, Meng YH, et al. Novel targets for treating ischemia-reperfusion injury in the liver[J]. Int J Mol Sci, 2018, 19(5): E1302. doi: 10.3390/ijms19051302
    [113] Xu CF, Yu CH, Li YM. Regulation of hepatic microRNA expression in response to ischemic preconditioning following ischemia/reperfusion injury in mice[J]. OMICS, 2009, 13(6): 513–520. doi: 10.1089/omi.2009.0035
    [114] Gehrau RC, Mas VR, Dumur CI, et al. Regulation of molecular pathways in ischemia-reperfusion injury after liver transplantation[J]. Transplantation, 2013, 96(10): 926–934. doi: 10.1097/TP.0b013e3182a20398
    [115] Mard SA, Akbari G, Dianat M, et al. Protective effects of crocin and zinc sulfate on hepatic ischemia-reperfusion injury in rats: a comparative experimental model study[J]. Biomed Pharmacother, 2017, 96: 48–55. doi: 10.1016/j.biopha.2017.09.123
    [116] Peralta C, Hotter G, Closa D, et al. Protective effect of preconditioning on the injury associated to hepatic ischemia-reperfusion in the rat: role of nitric oxide and adenosine[J]. Hepatology, 1997, 25(4): 934–937. doi: 10.1002/hep.510250424
    [117] Quarrie R, Cramer BM, Lee DS, et al. Ischemic preconditioning decreases mitochondrial proton leak and reactive oxygen species production in the postischemic heart[J]. J Surg Res, 2011, 165(1): 5–14. doi: 10.1016/j.jss.2010.09.018
    [118] Richards JA, Wigmore SJ, Devey LR. Heme oxygenase system in hepatic ischemia-reperfusion injury[J]. World J Gastroenterol, 2010, 16(48): 6068–6078. doi: 10.3748/wjg.v16.i48.6068
    [119] Liu AD, Fang HS, Wei WW, et al. Ischemic preconditioning protects against liver ischemia/reperfusion injury via heme oxygenase-1-mediated autophagy[J]. Crit Care Med, 2014, 42(12): e762–e771. doi: 10.1097/CCM.0000000000000659
    [120] Rüdiger HA, Graf R, Clavien PA. Sub-lethal oxidative stress triggers the protective effects of ischemic preconditioning in the mouse liver[J]. J Hepatol, 2003, 39(6): 972–977. doi: 10.1016/S0168-8278(03)00415-X
    [121] Rolo AP, Teodoro JS, Peralta C, et al. Prevention of I/R injury in fatty livers by ischemic preconditioning is associated with increased mitochondrial tolerance: the key role of ATPsynthase and mitochondrial permeability transition[J]. Transpl Int, 2009, 22(11): 1081–1090. doi: 10.1111/tri.2009.22.issue-11
    [122] Abu-Amara M, Yang SY, Quaglia A, et al. Role of endothelial nitric oxide synthase in remote ischemic preconditioning of the mouse liver[J]. Liver Transpl, 2011, 17(5): 610–619. doi: 10.1002/lt.v17.5
    [123] Koti RS, Seifalian AM, Davidson BR. Protection of the liver by ischemic preconditioning: a review of mechanisms and clinical applications[J]. Dig Surg, 2003, 20(5): 383–396. doi: 10.1159/000072064
    [124] Gurusamy KS, Kumar Y, Sharma D, et al. Ischaemic preconditioning for liver transplantation[J]. Cochrane Database Syst Rev, 2008, (1): CD006315.
    [125] Nadarajah L, Yaqoob MM, McCafferty K. Ischemic conditioning in solid organ transplantation: is it worth giving your right arm for?[J]. Curr Opin Nephrol Hypertens, 2017, 26(6): 467–476. doi: 10.1097/MNH.0000000000000367
    [126] Koneru B, Fisher A, He Y, et al. Ischemic preconditioning in deceased donor liver transplantation: a prospective randomized clinical trial of safety and efficacy[J]. Liver Transpl, 2005, 11(2): 196–202. doi: 10.1002/(ISSN)1527-6473
    [127] Koneru B, Shareef A, Dikdan G, et al. The ischemic preconditioning paradox in deceased donor liver transplantation-evidence from a prospective randomized single blind clinical trial[J]. Am J Transplant, 2007, 7(12): 2788–2796. doi: 10.1111/ajt.2007.7.issue-12
    [128] Theodoraki K, Karmaniolou I, Tympa A, et al. Beyond preconditioning: postconditioning as an alternative technique in the prevention of liver ischemia-reperfusion injury[J]. Oxid Med Cell Longev, 2016, 2016: 8235921.
    [129] Sun K, Liu ZS, Sun Q. Role of mitochondria in cell apoptosis during hepatic ischemia-reperfusion injury and protective effect of ischemic postconditioning[J]. World J Gastroenterol, 2004, 10(13): 1934–1938. doi: 10.3748/wjg.v10.i13.1934
    [130] Zhang WX, Yin W, Zhang L, et al. Preconditioning and postconditioning reduce hepatic ischemia-reperfusion injury in rats[J]. Hepatobiliary Pancreat Dis Int, 2009, 8(6): 586–590.
    [131] Yoon SY, Kim CY, Han HJ, et al. Protective effect of ischemic postconditioning against hepatic ischemic reperfusion injury in rat liver[J]. Ann Surg Treat Res, 2015, 88(5): 241–245. doi: 10.4174/astr.2015.88.5.241
    [132] Lin HC, Lee TK, Tsai CC, et al. Ischemic postconditioning protects liver from ischemia-reperfusion injury by modulating mitochondrial permeability transition[J]. Transplantation, 2012, 93(3): 265–271. doi: 10.1097/TP.0b013e31823ef335
    [133] Wang N, Lu JG, He XL, et al. Effects of ischemic postconditioning on reperfusion injury in rat liver grafts after orthotopic liver transplantation[J]. Hepatol Res, 2009, 39(4): 382–390. doi: 10.1111/hep.2009.39.issue-4
    [134] Kim WH, Lee JH, Ko JS, et al. Effect of remote ischemic postconditioning on patients undergoing living donor liver transplantation[J]. Liver Transpl, 2014, 20(11): 1383–1392. doi: 10.1002/lt.23960
    [135] Ricca L, Lemoine A, Cauchy F, et al. Ischemic postconditioning of the liver graft in adult liver transplantation[J]. Transplantation, 2015, 99(8): 1633–1643. doi: 10.1097/TP.0000000000000685
    [136] Schlegel AA, Kalisvaart M, Muiesan P. Machine perfusion in liver transplantation: an essential treatment or just an expensive toy?[J]. Minerva Anestesiol, 2018, 84(2): 236–245.
    [137] Liu Q, Vekemans K, Iania L, et al. Assessing warm ischemic injury of pig livers at hypothermic machine perfusion[J]. J Surg Res, 2014, 186(1): 379–389. doi: 10.1016/j.jss.2013.07.034
    [138] Monbaliu D, Liu Q, Libbrecht L, et al. Preserving the morphology and evaluating the quality of liver grafts by hypothermic machine perfusion: a proof-of-concept study using discarded human livers[J]. Liver Transpl, 2012, 18(12): 1495–1507. doi: 10.1002/lt.v18.12
    [139] Manekeller S, Schuppius A, Stegemann J, et al. Role of perfusion medium, oxygen and rheology for endoplasmic reticulum stress-induced cell death after hypothermic machine preservation of the liver[J]. Transpl Int, 2008, 21(2): 169–177.
    [140] Jain S, Xu HZ, Duncan H, et al. Ex-vivo study of flow dynamics and endothelial cell structure during extended hypothermic machine perfusion preservation of livers[J]. Cryobiology, 2004, 48(3): 322–332. doi: 10.1016/j.cryobiol.2004.01.010
    [141] Schlegel A, de Rougemont O, Graf R, et al. Protective mechanisms of end-ischemic cold machine perfusion in DCD liver grafts[J]. J Hepatol, 2013, 58(2): 278–286. doi: 10.1016/j.jhep.2012.10.004
    [142] Gallinat A, Efferz P, Paul A, et al. One or 4 h of " in-house” reconditioning by machine perfusion after cold storage improve reperfusion parameters in porcine kidneys[J]. Transpl Int, 2014, 27(11): 1214–1219. doi: 10.1111/tri.2014.27.issue-11
    [143] Guarrera JV, Henry SD, Samstein B, et al. Hypothermic machine preservation facilitates successful transplantation of " orphan” extended criteria donor livers[J]. Am J Transplant, 2015, 15(1): 161–169. doi: 10.1111/ajt.12958
    [144] Dutkowski P, Schlegel A, de Oliveira M, et al. HOPE for human liver grafts obtained from donors after cardiac death[J]. J Hepatol, 2014, 60(4): 765–772. doi: 10.1016/j.jhep.2013.11.023
    [145] Schlegel A, Muller X, Kalisvaart M, et al. Outcomes of DCD liver transplantation using organs treated by hypothermic oxygenated perfusion before implantation[J]. J Hepatol, 2019, 70(1): 50–57.
    [146] Ravikumar R, Jassem W, Mergental H, et al. Liver transplantation after ex vivo normothermic machine preservation: a phase 1 (first-in-man) clinical trial[J]. Am J Transplant, 2016, 16(6): 1779–1787. doi: 10.1111/ajt.13708
    [147] Xu HZ, Berendsen T, Kim K, et al. Excorporeal normothermic machine perfusion resuscitates pig DCD livers with extended warm ischemia[J]. J Surg Res, 2012, 173(2): e83–e88. doi: 10.1016/j.jss.2011.09.057
    [148] Mergental H, Perera MTPR, Laing RW, et al. Transplantation of declined liver allografts following normothermic ex-situ evaluation[J]. Am J Transplant, 2016, 16(11): 3235–3245. doi: 10.1111/ajt.13875