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  • Review Article
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Ischaemia–reperfusion injury in liver transplantation—from bench to bedside

Nature Reviews Gastroenterology & Hepatology volume 10, pages 79–89 (2013)Cite this article

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Abstract

Ischaemia–reperfusion injury (IRI) in the liver, a major complication of haemorrhagic shock, resection and transplantation, is a dynamic process that involves the two interrelated phases of local ischaemic insult and inflammation-mediated reperfusion injury. This Review highlights the latest mechanistic insights into innate–adaptive immune crosstalk and cell activation cascades that lead to inflammation-mediated injury in livers stressed by ischaemia–reperfusion, discusses progress in large animal experiments and examines efforts to minimize liver IRI in patients who have received a liver transplant. The interlinked signalling pathways in multiple hepatic cell types, the IRI kinetics and positive versus negative regulatory loops at the innate–adaptive immune interface are discussed. The current gaps in our knowledge and the pathophysiology aspects of IRI in which basic and translational research is still required are stressed. An improved appreciation of cellular immune events that trigger and sustain local inflammatory responses, which are ultimately responsible for organ injury, is fundamental to developing innovative strategies for treating patients who have received a liver transplant and developed ischaemia–reperfusion inflammation and organ dysfunction.

Key Points

  • The cellular damage incurred by organ procurement and preservation affects transplantation outcomes, contributes to donor organ shortage and represents a major risk factor for acute and chronic liver graft rejection

  • Liver ischaemia–reperfusion injury (IRI) is a local proinflammatory response that is mediated by the innate immune system

  • Several pattern recognition receptors, including Toll-like receptor (TLR)4, TLR9 and the inflammasome, are involved in liver immune activation against ischaemia–reperfusion in distinct cell types at different stages of IRI development

  • Different subsets of T cells participate in innate immune responses triggered by ischaemia–reperfusion via positive and negative co-stimulatory pathways

  • Studies of regulated hepatic reperfusion in large animals might lead to successful clinical use of liver grafts procured from extended criteria donors and donation after cardiac death

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Figure 1: The distinct stages of liver ischaemia–reperfusion injury.
Figure 2: A scheme of liver immune activation against ischaemia–reperfusion injury.
Figure 3: Regulated hepatic reperfusion and splenojugular venovenous bypass circuits.

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Change history

  • 11 January 2013

    In the version of this article initially published online the animal model in Figure 3 was portrayed incorrectly. The error has been corrected for the print, HTML and PDF versions of the article.

References

  1. Wertheim, J. A., Petrowsky, H., Saab, S., Kupiec-Weglinski, J. W. & Busuttil, R. W. Major challenges limiting liver transplantation in the United States. Am. J. Transplant. 11, 1773–1784 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. US Department of Health and Human Services. Organ Procurement and Transplantation Network [online], (2012).

  3. Lentsch, A. B., Kato, A., Yoshidome, H., McMasters, K. M. & Edwards, M. J. Inflammatory mechanisms and therapeutic strategies for warm hepatic ischemia/reperfusion injury. Hepatology 32, 169–173 (2000).

    Article  CAS  PubMed  Google Scholar 

  4. Zhai, Y., Busuttil, R. W. & Kupiec-Weglinski, J. W. Liver ischemia and reperfusion injury: new insights into mechanisms of innate-adaptive immune-mediated tissue inflammation. Am. J. Transplant. 11, 1563–1569 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Eltzchig, H. K. & Eckle, T. Ischemia and reperfusion—from mechanism to translation. Nat. Med. 17, 1391–1401 (2011).

    Article  CAS  Google Scholar 

  6. Jaeschke, H. & Woolbright, B. L. Current strategies to minimize ischemia-reperfusion injury by targeting reactive oxygen species. Transplant. Rev. 26, 103–114 (2012).

    Article  Google Scholar 

  7. Sacks, S. H. & Zhou, W. The role of complement in the early immune response to transplantation. Nat. Rev. Immunol. 12, 431–442 (2012).

    Article  CAS  PubMed  Google Scholar 

  8. Abu-Amara, M. et al. Liver ischemia/reperfusion injury: Processes in inflammatory networks—a review. Liver Transpl. 16, 1016–1032 (2010).

    Article  PubMed  Google Scholar 

  9. Rougemont, O., Lehmann, K. & Clavien, P. A. Preconditioning, organ preservation, and postconditioning to prevent ischemia-reperfusion injury to the liver. Liver Transpl. 15, 1172–1182 (2009).

    Article  PubMed  Google Scholar 

  10. Selzner, N., Rudiger, H., Graf, R. & Clavien, P. A. Protective strategies against ischemic injury of the liver. Gastroenterology 125, 917–936 (2003).

    Article  CAS  PubMed  Google Scholar 

  11. Richards, J. A., Wigmore, S. J. & Devey, L. R. Heme oxygenase system in hepatic ischemia-reperfusion injury. World J. Gastroenterol. 16, 6068–6078 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Ikeda, T. et al. Ischemic injury in liver transplantation: difference in injury sites between warm and cold ischemia in rats. Hepatology 16, 454–461 (1992).

    Article  CAS  PubMed  Google Scholar 

  13. Shen, X. D. et al. Disruption of type-I IFN pathway ameliorates preservation damage in mouse orthotopic liver transplantation via HO-1 dependent mechanism. Am. J. Transplant. 12, 1730–1739 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Shen, X. D. et al. Inflammatory responses in a new mouse model of prolonged hepatic cold ischemia followed by arterialized orthotopic liver transplantation. Liver Transpl. 11, 1273–1281 (2005).

    Article  PubMed  Google Scholar 

  15. Land, W. et al. The beneficial effect of human recombinant superoxide dismutase on acute and chronic rejection events in recipients of cadaveric renal transplants. Transplantation 57, 211–217 (1994).

    Article  CAS  PubMed  Google Scholar 

  16. Land, W. G. The role of postischemic reperfusion injury and other nonantigen-dependent inflammatory pathways in transplantation. Transplantation 79, 505–514 (2005).

    Article  PubMed  Google Scholar 

  17. Beg, A. A. Endogenous ligands of Toll-like receptors: implications for regulating inflammatory and immune responses. Trends Immunol. 23, 509–512 (2002).

    Article  CAS  PubMed  Google Scholar 

  18. Fox-Marsh, A. & Harrison, L. C. Emerging evidence that molecules expressed by mammalian tissue grafts are recognized by the innate immune system. J. Leukoc. Biol. 71, 401–409 (2002).

    CAS  PubMed  Google Scholar 

  19. Rifkin, I. R., Leadbetter, E. A., Busconi, L., Viglianti, G. & Marshak-Rothstein, A. Toll-like receptors, endogenous ligands, and systemic autoimmune disease. Immunol. Rev. 204, 27–42 (2005).

    Article  CAS  PubMed  Google Scholar 

  20. Lotze, M. T. et al. The grateful dead: damage-associated molecular pattern molecules and reduction/oxidation regulate immunity. Immunol. Rev. 220, 60–81 (2007).

    Article  CAS  PubMed  Google Scholar 

  21. Srikrishna, G. & Freeze, H. H. Endogenous damage-associated molecular pattern molecules at the crossroads of inflammation and cancer. Neoplasia 11, 615–628 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Kawai, T. & Akira, S. Toll-like receptor and RIG-I-like receptor signaling. Ann. NY Acad. Sci. 1143, 1–20 (2008).

    Article  CAS  PubMed  Google Scholar 

  23. Takeuchi, O. & Akira, S. Pattern recognition receptors and inflammation. Cell 140, 805–820 (2010).

    Article  CAS  PubMed  Google Scholar 

  24. Akira, S. & Takeda, K. Toll-like receptor signalling. Nat. Rev. Immunol. 4, 499–511 (2004).

    Article  CAS  PubMed  Google Scholar 

  25. Trinchieri, G. & Sher, A. Cooperation of Toll-like receptor signals in innate immune defence. Nat. Rev. Immunol. 7, 179–190 (2007).

    Article  CAS  PubMed  Google Scholar 

  26. Baccala, R. et al. Sensors of the innate immune system: their mode of action. Nat. Rev. Rheumatol. 5, 448–456 (2009).

    Article  CAS  PubMed  Google Scholar 

  27. Tsung, A. et al. Hepatic ischemia/reperfusion injury involves functional TLR4 signaling in nonparenchymal cells. J. Immunol. 175, 7661–7668 (2005).

    Article  CAS  PubMed  Google Scholar 

  28. Wu, H. S. et al. Toll-like receptor 4 involvement in hepatic ischemia/reperfusion injury in mice. Hepatobiliary Pancreat. Dis. Int. 3, 250–253 (2004).

    CAS  PubMed  Google Scholar 

  29. Zhai, Y. et al. Cutting edge: TLR4 activation mediates liver ischemia/reperfusion inflammatory response via IFN regulatory factor 3-dependent MyD88-independent pathway. J. Immunol. 173, 7115–7119 (2004).

    Article  CAS  PubMed  Google Scholar 

  30. Leemans, J. C. et al. Renal-associated TLR2 mediates ischemia/reperfusion injury in the kidney. J. Clin. Invest. 115, 2894–2903 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Arslan, F. et al. Myocardial ischemia/reperfusion injury is mediated by leukocytic Toll-like receptor-2 and reduced by systemic administration of a novel anti-Toll-like receptor-2 antibody. Circulation 121, 80–90 (2010).

    Article  CAS  PubMed  Google Scholar 

  32. Shen, X. D. et al. Absence of toll-like receptor 4 (TLR4) signaling in the donor organ reduces ischemia and reperfusion injury in a murine liver transplantation model. Liver Transpl. 13, 1435–1443 (2007).

    Article  PubMed  Google Scholar 

  33. Ellett, J. D. et al. Toll-like receptor 4 is a key mediator of murine steatotic liver warm ischemia/reperfusion injury. Liver Transpl. 15, 1101–1109 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  34. Hui, W., Jinxiang, Z., Heshui, W., Zhuoya, L. & Qichang, Z. Bone marrow and non-bone marrow TLR4 regulates hepatic ischemia/reperfusion injury. Biochem. Biophys. Res. Commun. 389, 328–332 (2009).

    Article  CAS  PubMed  Google Scholar 

  35. Wu, H. et al. TLR4 activation mediates kidney ischemia/reperfusion injury. J. Clin. Invest. 117, 2847–2859 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Pulskens, W. P. et al. Toll-like receptor-4 coordinates the innate immune response of the kidney to renal ischemia/reperfusion injury. PLoS ONE 3, e3596 (2008).

  37. Kaczorowski, D. J. et al. Mechanisms of Toll-like receptor 4 (TLR4)-mediated inflammation after cold ischemia/reperfusion in the heart. Transplantation 87, 1455–1463 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Shigeoka, A. A. et al. TLR2 is constitutively expressed within the kidney and participates in ischemic renal injury through both MyD88-dependent and -independent pathways. J. Immunol. 178, 6252–6258 (2007).

    Article  CAS  PubMed  Google Scholar 

  39. Broad, A., Kirby, J. A. & Jones, D. E. Toll-like receptor interactions: tolerance of MyD88-dependent cytokines but enhancement of MyD88-independent interferon-beta production. Immunology 120, 103–111 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Biswas, S. K. & Lopez-Collazo, E. Endotoxin tolerance: new mechanisms, molecules and clinical significance. Trends Immunol. 30, 475–487 (2009).

    Article  CAS  PubMed  Google Scholar 

  41. Martin, M., Rehani, K., Jope, R. S. & Michalek, S. M. Toll-like receptor-mediated cytokine production is differentially regulated by glycogen synthase kinase 3. Nat. Immunol. 6, 777–784 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Ren, F. et al. Inhibition of glycogen synthase kinase 3 beta ameliorates liver ischemia reperfusion injury by way of an interleukin-10-mediated immune regulatory mechanism. Hepatology 54, 687–696 (2011).

    Article  CAS  PubMed  Google Scholar 

  43. Jacob, A. I., Goldberg, P. K., Bloom, N., Degenshein, G. A. & Kozinn, P. J. Endotoxin and bacteria in portal blood. Gastroenterology 72, 1268–1270 (1977).

    CAS  PubMed  Google Scholar 

  44. Fiorini, R. N. et al. Anti-endotoxin monoclonal antibodies are protective against hepatic ischemia/reperfusion injury in steatotic mice. Am. J. Transplant. 4, 1567–1573 (2004).

    Article  CAS  PubMed  Google Scholar 

  45. Zhai, Y. et al. Evidence for the pivotal role of endogenous toll-like receptor 4 ligands in liver ischemia and reperfusion injury. Transplantation 85, 1016–1022 (2008).

    Article  CAS  PubMed  Google Scholar 

  46. Erridge, C. Endogenous ligands of TLR2 and TLR4: agonists or assistants? J. Leukoc. Biol. 87, 989–999 (2010).

    Article  CAS  PubMed  Google Scholar 

  47. Tsung, A. et al. The nuclear factor HMGB1 mediates hepatic injury after murine liver ischemia-reperfusion. J. Exp. Med. 201, 1135–1143 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Tsung, A. et al. HMGB1 release induced by liver ischemia involves Toll-like receptor 4 dependent reactive oxygen species production and calcium-mediated signaling. J. Exp. Med. 204, 2913–2923 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Hreggvidsdottir, H. S. et al. The alarmin HMGB1 acts in synergy with endogenous and exogenous danger signals to promote inflammation. J. Leukoc. Biol. 86, 655–662 (2009).

    Article  CAS  PubMed  Google Scholar 

  50. Qin, Y. H. et al. HMGB1 enhances the proinflammatory activity of lipopolysaccharide by promoting the phosphorylation of MAPK p38 through receptor for advanced glycation end products. J. Immunol. 183, 6244–6250 (2009).

    Article  CAS  PubMed  Google Scholar 

  51. Zeng, S. et al. Receptor for advanced glycation end product (RAGE)-dependent modulation of early growth response-1 in hepatic ischemia/reperfusion injury. J. Hepatol. 50, 929–936 (2009).

    Article  CAS  PubMed  Google Scholar 

  52. Zeng, S. et al. Blockade of receptor for advanced glycation end product (RAGE) attenuates ischemia and reperfusion injury to the liver in mice. Hepatology 39, 422–432 (2004).

    Article  CAS  PubMed  Google Scholar 

  53. Dhupar, R. et al. Interferon regulatory factor 1 mediates acetylation and release of high mobility group Box 1 from hepatocytes during murine liver ischemia-reperfusion injury. Shock 35, 293–301 (2011).

    Article  CAS  PubMed  Google Scholar 

  54. Ueki, S. et al. Critical role of interferon regulatory factor-1 in murine liver transplant ischemia reperfusion injury. Hepatology 51, 1692–1701 (2010).

    Article  CAS  PubMed  Google Scholar 

  55. Schiraldi, M. et al. HMGB1 promotes recruitment of inflammatory cells to damaged tissues by forming a complex with CXCL12 and signaling via CXCR4. J. Exp. Med. 209, 551–563 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Bamboat, Z. M. et al. Toll-like receptor 9 inhibition confers protection from liver ischemia-reperfusion injury. Hepatology 51, 621–632 (2009).

    Article  CAS  Google Scholar 

  57. Huang, H. et al. Endogenous histones function as alarmins in sterile inflammatory liver injury through Toll-like receptor 9 in mice. Hepatology 54, 999–1008 (2011).

    Article  CAS  PubMed  Google Scholar 

  58. Cavassani, K. A. et al. TLR3 is an endogenous sensor of tissue necrosis during acute inflammatory events. J. Exp. Med. 205, 2609–2621 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. McDonald, B. et al. Intravascular danger signals guide neutrophils to sites of sterile inflammation. Science 330, 362–366 (2010).

    Article  CAS  PubMed  Google Scholar 

  60. Zhu, P. et al. Gene silencing of NALP3 protects against liver ischemia-reperfusion injury in mice. Hum. Gene Ther. 22, 853–864 (2011).

    Article  CAS  PubMed  Google Scholar 

  61. Menzel, C. L. et al. Caspase-1 is hepatoprotective during trauma and hemorrhagic shock by reducing liver injury and inflammation. Mol. Med. 17, 1031–1038 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Suzuki, S., Toledo-Pereyra, L. H., Rodriguez, F. J. & Cejalvo, D. Neutrophil infiltration as an important factor in liver ischemia and reperfusion injury. Modulating effects of FK506 and cyclosporine. Transplantation 55, 1265–1272 (1993).

    Article  CAS  PubMed  Google Scholar 

  63. Zwacka, R. M. et al. CD4(+) T-lymphocytes mediate ischemia/reperfusion-induced inflammatory responses in mouse liver. J. Clin. Invest. 100, 279–289 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Rabb, H. et al. Pathophysiological role of T lymphocytes in renal ischemia-reperfusion injury in mice. Am. J. Physiol. Renal Physiol. 279, F525–F531 (2000).

    Article  CAS  PubMed  Google Scholar 

  65. Shen, X. D. et al. CD154-CD40 T-cell costimulation pathway is required in the mechanism of hepatic ischemia/reperfusion injury, and its blockade facilitates and depends on heme oxygenase-1 mediated cytoprotection. Transplantation 74, 315–319 (2002).

    Article  CAS  PubMed  Google Scholar 

  66. Burne, M. J. et al. Identification of the CD4+ T cell as a major pathogenic factor in ischemic acute renal failure. J. Clin. Invest. 108, 1283–1290 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Takada, M., Chandraker, A., Nadeau, K. C., Sayegh, M. H. & Tilney, N. L. The role of the B7 costimulatory pathway in experimental cold ischemia/reperfusion injury. J. Clin. Invest. 100, 1199–1203 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Shen, X. D. et al. Stat4 and Stat6 signaling in hepatic ischemia/reperfusion injury in mice: HO-1 dependence of Stat4 disruption-mediated cytoprotection. Hepatology 37, 296–303 (2003).

    Article  CAS  PubMed  Google Scholar 

  69. Kono, H. et al. Role of IL-17A in neutrophil recruitment and hepatic injury after warm ischemia-reperfusion mice. J. Immunol. 187, 4818–4825 (2011).

    Article  CAS  PubMed  Google Scholar 

  70. Caldwell, C. C., Tschoep, J. & Lentsch, A. B. Lymphocyte function during hepatic ischemia/reperfusion injury. J. Leukoc. Biol. 82, 457–464 (2007).

    Article  CAS  PubMed  Google Scholar 

  71. Radaeva, S., Sun, R., Pan, H. N., Hong, F. & Gao, B. Interleukin 22 (IL-22) plays a protective role in T cell-mediated murine hepatitis: IL-22 is a survival factor for hepatocytes via STAT3 activation. Hepatology 39, 1332–1342 (2004).

    Article  CAS  PubMed  Google Scholar 

  72. Kreymborg, K. et al. IL-22 is expressed by TH17 cells in an IL-23-dependent fashion, but not required for the development of autoimmune encephalomyelitis. J. Immunol. 179, 8098–8104 (2007).

    Article  CAS  PubMed  Google Scholar 

  73. Ki, S. H. et al. Interleukin-22 treatment ameliorates alcoholic liver injury in a murine model of chronic-binge ethanol feeding: role off signal transducer and activator of transcription 3. Hepatology 52, 1291–1300 (2010).

    Article  CAS  PubMed  Google Scholar 

  74. Wolk, K., Witte, E., Witte, K., Warszawska, K. & Sabat, R. Biology of interleukin-22. Semin. Immunopathol. 32, 17–31 (2010).

    Article  CAS  PubMed  Google Scholar 

  75. Chestovich, P. J. et al. Interleukin-22: implications for liver ischemia-reperfusion injury. Transplantation 93, 485–492 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Knolle, P. et al. Human Kupffer cells secrete IL-10 in response to lipopolysaccharide (LPS) challenge. J. Hepatol. 22, 226–229 (1995).

    Article  CAS  PubMed  Google Scholar 

  77. De Creus, A. et al. Low TLR4 expression by liver dendritic cells correlates with reduced capacity to activate allogeneic T cells in response to endotoxin. J. Immunol. 174, 2037–2045 (2005).

    Article  CAS  PubMed  Google Scholar 

  78. Bamboat, Z. M. et al. Conventional DCs reduce liver ischemia/reperfusion injury in mice via IL-10 secretion. J. Clin. Invest. 120, 559–569 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Kuchroo, V. K., Meyers, J. H., Umetsu, D. T. & DeKruyff, R. H. TIM family of genes in immunity and tolerance. Adv. Immunol. 91, 227–249 (2006).

    Article  CAS  PubMed  Google Scholar 

  80. Uchida, Y. et al. The emerging role of T cell immunoglobulin mucin-1 in the mechanism of liver ischemia and reperfusion injury in the mouse. Hepatology 51, 1363–1372 (2010).

    Article  CAS  PubMed  Google Scholar 

  81. Rong, S. et al. The TIM-1:TIM-4 pathway enhances renal ischemia-reperfusion injury. J. Am. Soc. Nephrol. 22, 484–495 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Uchida, Y. et al. T-cell immunoglobulin mucin-3 determines severity of liver ischemia/reperfusion injury in mice in a TLR4-dependent manner. Gastroenterology 139, 2195–2206 (2010).

    Article  CAS  PubMed  Google Scholar 

  83. Ji, H. et al. Programmed death-1/B7-H1 negative costimulation protects mouse liver against ischemia and reperfusion injury. Hepatology 52, 1380–1389 (2010).

    Article  CAS  PubMed  Google Scholar 

  84. Ueki, S. et al. Hepatic B7 Homolog 1 expression is essential for controlling cold ischemia/reperfusion injury after mouse liver transplantation. Hepatology 54, 216–228 (2011).

    Article  CAS  PubMed  Google Scholar 

  85. Shen, X. et al. CD4 T cells promote tissue inflammation via CD40 signaling without de novo activation in a murine model of liver ischemia/reperfusion injury. Hepatology 50, 1537–1546 (2009).

    Article  CAS  PubMed  Google Scholar 

  86. Lappas, C. M., Day, Y. J., Marshall, M. A., Engelhard, V. H. & Linden, J. Adenosine A2A receptor activation reduces hepatic ischemia reperfusion injury by inhibiting CD1d-dependent NKT cell activation. J. Exp. Med. 203, 2639–2648 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Arrenberg, P., Maricic, I. & Kumar, V. Sulfatide-mediated activation of type II natural killer T cells prevents hepatic ischemic reperfusion injury in mice. Gastroenterology 140, 646–655 (2011).

    Article  CAS  PubMed  Google Scholar 

  88. Beldi, G. et al. Deletion of CD39 on natural killer cells attenuates hepatic ischemia/reperfusion injury in mice. Hepatology 51, 1702–1711 (2010).

    Article  CAS  PubMed  Google Scholar 

  89. Magliocca, J. F. et al. Extracorporeal support for organ donation after cardiac death effectively expands the donor pool. J. Trauma 58, 1095–1101 (2005).

    Article  PubMed  Google Scholar 

  90. Fondevila, C. et al. Liver transplant using donors after unexpected cardiac death: novel preservation protocol and acceptance criteria. Am. J. Transplant. 7, 1849–1855 (2007).

    Article  CAS  PubMed  Google Scholar 

  91. Hong, J. C. et al. Regulated hepatic reperfusion mitigates ischemia and reperfusion injury and improves survival after prolonged liver warm ischemia: a pilot study on a novel concept of organ resuscitation in a large animal model. J. Am. Coll. Surg. 214, 505–515 (2012).

    Article  PubMed  Google Scholar 

  92. Garcia-Valdecasas, J. C. et al. Liver conditioning after cardiac arrest: the use of normothermic recirculation in an experimental animal model. Transpl. Int. 11, 424–432 (1998).

    Article  CAS  PubMed  Google Scholar 

  93. Fondevila, C. et al. Superior preservation of DCD livers with continuous normothermic perfusion. Ann. Surg. 254, 1000–1007 (2011).

    Article  PubMed  Google Scholar 

  94. Monbaliu, D. & Brassil, J. Machine perfusion of the liver: past, present and future. Curr. Opin. Organ. Transplant. 15, 160–166 (2010).

    Article  PubMed  Google Scholar 

  95. Butler, A. J. et al. Successful extracorporeal porcine liver perfusion for 72 hr. Transplantation 73, 1212–1218 (2002).

    Article  CAS  PubMed  Google Scholar 

  96. Schon, M. R. et al. Liver transplantation after organ preservation with normothermic extracorporeal perfusion. Ann. Surg. 233, 114–123 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Brockmann, J. et al. Normothermic perfusion: a new paradigm for organ preservation. Ann. Surg. 250, 1–6 (2009).

    Article  PubMed  Google Scholar 

  98. de Rougemont, O. et al. One hour hypothermic oxygenated perfusion (HOPE) protects nonviable liver allografts donated after cardiac death. Ann. Surg. 250, 674–683 (2009).

    Article  PubMed  Google Scholar 

  99. Guarrera, J. V. et al. Hypothermic machine preservation in human liver transplantation: the first clinical series. Am. J. Transplant. 10, 372–381 (2010).

    Article  CAS  PubMed  Google Scholar 

  100. Minor, T., Manekeller, S., Sioutis, M. & Dombrowski, F. Endoplasmic and vascular surface activation during organ preservation: refining upon the benefits of machine perfusion. Am. J. Transplant. 6, 1355–1366 (2006).

    Article  CAS  PubMed  Google Scholar 

  101. Goto, M. et al. Hepatic tissue oxygenation as a predictive indicator of ischemia-reperfusion liver injury. Hepatology 15, 432–437 (1992).

    Article  CAS  PubMed  Google Scholar 

  102. Kamiike, W. et al. Correlation between cellular ATP level and bile excretion in the rat liver. Transplantation 39, 50–55 (1985).

    Article  CAS  PubMed  Google Scholar 

  103. Monden, M. & Fortner, J. G. Twenty-four- and 48-hour canine liver preservation by simple hypothermia with prostacyclin. Ann. Surg. 196, 38–42 (1982).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Ghonem, N. et al. Treprostinil, a prostacyclin analog, ameliorates ischemia-reperfusion injury in rat orthotopic liver transplantation. Am. J. Transplant. 11, 2508–2516 (2011).

    Article  CAS  PubMed  Google Scholar 

  105. Klein, M. et al. Preconditioning of donor livers with prostaglandin I2 before retrieval decreases hepatocellular ischemia-reperfusion injury. Transplantation 67, 1128–1132 (1999).

    Article  CAS  PubMed  Google Scholar 

  106. Kotsch, K. et al. Methylprednisolone therapy in deceased donors reduces inflammation in the donor liver and improves outcome after liver transplantation: a prospective randomized controlled trial. Ann. Surg. 248, 1042–1050 (2008).

    Article  PubMed  Google Scholar 

  107. Weiss, S. et al. Brain death activates donor organs and is associated with a worse I/R injury after liver transplantation. Am. J. Transplant. 7, 1584–1593 (2007).

    Article  CAS  PubMed  Google Scholar 

  108. Mehrabi, A. et al. Thymoglobulin and ischemia reperfusion injury in kidney and liver transplantation. Nephrol. Dial. Transplant. 22 (Suppl. 8), viii54–viii60 (2007).

    PubMed  Google Scholar 

  109. Goggins, W. C. et al. A prospective randomized clinical trial of intraoperative versus postoperative thymoglobulin in adult cadaveric renal transplant recipients. Transplantation 76, 798–802 (2003).

    Article  CAS  PubMed  Google Scholar 

  110. Bogetti, D. et al. Thymoglobulin induction protects liver allografts from ischemia/reperfusion injury. Clin. Transplant. 19, 507–511 (2005).

    Article  PubMed  Google Scholar 

  111. Baskin-Bey, E. S. et al. Clinical trial of the pan-caspase inhibitor, IDN-6556, in human liver preservation injury. Am. J. Transplant. 7, 218–225 (2007).

    Article  CAS  PubMed  Google Scholar 

  112. Alvarado-Kristensson, M. et al. p38-MAPK signals survival by phosphorylation of caspase-8 and caspase-3 in human neutrophils. J. Exp. Med. 199, 449–458 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Busuttil, R. W. et al. rPSGL-Ig for improvement of early liver allograft function: a double-blind, placebo-controlled, single-center phase II study. Am. J. Transplant. 11, 786–797 (2011).

    Article  CAS  PubMed  Google Scholar 

  114. Yang, J., Galipeau, J., Kozak, C. A., Furie, B. C. & Furie, B. Mouse P-selectin glycoprotein ligand-1: molecular cloning, chromosomal localization, and expression of a functional P-selectin receptor. Blood 87, 4176–4186 (1996).

    CAS  PubMed  Google Scholar 

  115. Dulkanchainun, T. S. et al. Reduction of hepatic ischemia/reperfusion injury by a soluble P-selectin glycoprotein ligand-1. Ann. Surg. 227, 832–840 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Amersi, F. et al. P-selectin glycoprotein ligand-1 (rPSGL-Ig)-mediated blockade of CD62 selectin molecules protects rat steatotic liver grafts from ischemia/reperfusion injury. Am. J. Transplant. 2, 600–608 (2002).

    Article  CAS  PubMed  Google Scholar 

  117. Tsuchihashi, S. 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. Immunol. 176, 616–624 (2006).

    Article  CAS  PubMed  Google Scholar 

  118. Lang, J. D. et al. Inhaled NO accelerates restoration of liver function in adults following orthotopic liver transplantation. J. Clin. Invest. 117, 2583–2591 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. US National Library of Medicine. ClinicalTrials.gov [online], (2012).

  120. US National Library of Medicine. ClinicalTrials.gov [online], (2009).

  121. US National Library of Medicine. ClinicalTrials.gov [online], (2012).

  122. US National Library of Medicine. ClinicalTrials.gov [online], (2012).

  123. Kristo, I. et al. Effect of intraportal infusion of tacrolimus on ischaemic reperfusion injury in orthotopic liver transplantation: a randomized controlled trial. Transpl. Int. 24, 912–919 (2011).

    Article  CAS  PubMed  Google Scholar 

  124. Khan, A. W. et al. A prospective randomized trial of N-acetyl cysteine administration during cold preservation of the donor liver for transplantation. Ann. Hepatol. 4, 121–126 (2005).

    CAS  PubMed  Google Scholar 

  125. Hilmi, I. A. et al. N-acetylcysteine does not prevent hepatorenal ischaemia-reperfusion injury in patients undergoing orthotopic liver transplantation. Nephrol. Dial Transplant. 25, 2328–2333 (2010).

    Article  CAS  Google Scholar 

  126. ISRCTN Register. HEGPOL: Randomised, placebo controlled, multicenter, double-blind clinical trial to investigate hepatoprotective effects of glycine in the postoperative phase of liver transplantation [online], (2012).

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Authors and Affiliations

  1. Division of Liver and Pancreas Transplantation, Department of Surgery, The Dumont-UCLA Transplant Center, David Geffen School of Medicine at UCLA, 77–120 CHS, 10833 Le Conte Avenue, Los Angeles, 90095, CA, USA

    Yuan Zhai, Henrik Petrowsky, Johnny C. Hong, Ronald W. Busuttil & Jerzy W. Kupiec-Weglinski

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  1. Yuan Zhai
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  2. Henrik Petrowsky
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  3. Johnny C. Hong
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  4. Ronald W. Busuttil
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  5. Jerzy W. Kupiec-Weglinski
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All authors contributed equally to researching data for the article, discussions of content and reviewing and editing the manuscript. Y. Zhai, H. Petrowsky, J. C. Hong and J. W. Kupiec-Weglinski wrote the article.

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Correspondence to Jerzy W. Kupiec-Weglinski.

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Zhai, Y., Petrowsky, H., Hong, J. et al. Ischaemia–reperfusion injury in liver transplantation—from bench to bedside. Nat Rev Gastroenterol Hepatol 10, 79–89 (2013). https://doi.org/10.1038/nrgastro.2012.225

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