Hepatic Ischemia/Reperfusion Injury

  • Callisia N. Clarke
  • Amit D. Tevar
  • Alex B. Lentsch
Part of the Molecular Pathology Library book series (MPLB, volume 5)


Hepatic ischemia/reperfusion (I/R) injury is a frequently encountered complication in a variety of clinical scenarios including liver transplantation, major hepatic resection, abdominal trauma surgery and hemorrhagic shock. In the late nineteenth century, Dr. James Hogarth Pringle, a celebrated surgeon, developed a technique in which the blood flow through the hepatic artery and portal vein was occluded in order to achieve hemostasis during abdominal surgery for hemorrhage associated with liver trauma. This technique was later named the Pringle maneuver. With the growth in the field of hepatobiliary surgery, this technique of total vascular occlusion was adapted and has enabled surgeons to perform complex procedures such as orthotropic liver transplantation and large liver resections and repairs that otherwise would have resulted in massive hemorrhage and certain death.


Liver Injury Kupffer Cell Neutrophil Recruitment Cold Ischemia Secretory Leukocyte Protease Inhibitor 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Jaeschke H, Farhood A, Smith CW. Neutrophils contribute to ischemia/reperfusion injury in rat liver in vivo. FASEB J. 1990;4(15):3355–9.PubMedGoogle Scholar
  2. 2.
    Jaeschke H et al. Complement activates Kupffer cells and neutrophils during reperfusion after hepatic ischemia. Am J Physiol. 1993;264(4 Pt 1):G801–9.PubMedGoogle Scholar
  3. 3.
    Lemasters JJ, Necrapoptosis V. and the mitochondrial permeability transition: shared pathways to necrosis and apoptosis. Am J Physiol. 1999;276(1 Pt 1):G1–6.PubMedGoogle Scholar
  4. 4.
    Lemasters JJ et al. The mitochondrial permeability transition in toxic, hypoxic and reperfusion injury. Mol Cell Biochem. 1997;174(1–2):159–65.PubMedCrossRefGoogle Scholar
  5. 5.
    Malhi H, Gores GJ, Lemasters JJ. Apoptosis and necrosis in the liver: a tale of two deaths? Hepatology. 2006;43(2 Suppl 1):S31–44.PubMedCrossRefGoogle Scholar
  6. 6.
    Jaeschke H et al. Superoxide generation by neutrophils and Kupffer cells during in vivo reperfusion after hepatic ischemia in rats. J Leukoc Biol. 1992;52(4):377–82.PubMedGoogle Scholar
  7. 7.
    Jaeschke H, Farhood A. Neutrophil and Kupffer cell-induced oxidant stress and ischemia-reperfusion injury in rat liver. Am J Physiol. 1991;260(3 Pt 1):G355–62.PubMedGoogle Scholar
  8. 8.
    Liu P et al. Activation of Kupffer cells and neutrophils for reactive oxygen formation is responsible for endotoxin-enhanced liver injury after hepatic ischemia. Shock. 1995;3(1):56–62.PubMedGoogle Scholar
  9. 9.
    Shiratori Y et al. Modulation of ischemia-reperfusion-induced hepatic injury by Kupffer cells. Dig Dis Sci. 1994;39(6):1265–72.PubMedCrossRefGoogle Scholar
  10. 10.
    Jaeschke H, Smith CW. Mechanisms of neutrophil-induced parenchymal cell injury. J Leukoc Biol. 1997;61(6):647–53.PubMedGoogle Scholar
  11. 11.
    Jaeschke H et al. Mechanisms of inflammatory liver injury: adhesion molecules and cytotoxicity of neutrophils. Toxicol Appl Pharmacol. 1996;139(2):213–26.PubMedCrossRefGoogle Scholar
  12. 12.
    Jaeschke H, Smith CV, Mitchell JR. Reactive oxygen species during ischemia-reflow injury in isolated perfused rat liver. J Clin Invest. 1988;81(4):1240–6.PubMedCrossRefGoogle Scholar
  13. 13.
    Jaeschke H. Reactive oxygen and mechanisms of inflammatory liver injury. J Gastroenterol Hepatol. 2000;15(7):718–24.PubMedCrossRefGoogle Scholar
  14. 14.
    Ghosh S, May MJ, Kopp EB. NF-kappa B and Rel proteins: evolutionarily conserved mediators of immune responses. Annu Rev Immunol. 1998;16:225–60.PubMedCrossRefGoogle Scholar
  15. 15.
    May MJ, Ghosh S. Signal transduction through NF-kappa B. Immunol Today. 1998;19(2):80–8.PubMedCrossRefGoogle Scholar
  16. 16.
    Perkins ND et al. Distinct combinations of NF-kappa B subunits determine the specificity of transcriptional activation. Proc Natl Acad Sci U S A. 1992;89(5):1529–33.PubMedCrossRefGoogle Scholar
  17. 17.
    Liu J et al. Specific NF-kappa B subunits act in concert with Tat to stimulate human immunodeficiency virus type 1 transcription. J Virol. 1992;66(6):3883–7.PubMedGoogle Scholar
  18. 18.
    Scheidereit C. IkappaB kinase complexes: gateways to NF-kappaB activation and transcription. Oncogene. 2006;25(51):6685–705.PubMedCrossRefGoogle Scholar
  19. 19.
    Mercurio F et al. IKK-1 and IKK-2: cytokine-activated Ikappa B kinases essential for NF-kappa B activation. Science. 1997;278(5339):860–6.PubMedCrossRefGoogle Scholar
  20. 20.
    Chen Z et al. Signal-induced site-specific phosphorylation targets I kappa B alpha to the ubiquitin-proteasome pathway. Genes Dev. 1995;9(13):1586–97.PubMedCrossRefGoogle Scholar
  21. 21.
    Imbert V et al. Tyrosine phosphorylation of I kappa B-alpha activates NF-kappa B without proteolytic degradation of I kappa B-alpha. Cell. 1996;86(5):787–98.PubMedCrossRefGoogle Scholar
  22. 22.
    Fan C et al. Tyrosine phosphorylation of I kappa B alpha activates NF kappa B through a redox-regulated and c-Src-dependent mechanism following hypoxia/reoxygenation. J Biol Chem. 2003;278(3):2072–80.PubMedCrossRefGoogle Scholar
  23. 23.
    Zwacka RM et al. Ischemia/reperfusion injury in the liver of BALB/c mice activates AP-1 and nuclear factor kappaB independently of Ikappa B degradation. Hepatology. 1998;28(4):1022–30.PubMedCrossRefGoogle Scholar
  24. 24.
    Okaya T, Lentsch AB. Hepatic expression of S32A/S36A IkappaBalpha does not reduce postischemic liver injury. J Surg Res. 2005;124(2):244–9.PubMedCrossRefGoogle Scholar
  25. 25.
    Koong AC, Chen EY, Giaccia AJ. Hypoxia causes the activation of nuclear factor kappa B through the phosphorylation of I kappa B alpha on tyrosine residues. Cancer Res. 1994;54(6):1425–30.PubMedGoogle Scholar
  26. 26.
    Sun SC et al. NF-kappa B controls expression of inhibitor I kappa B alpha: evidence for an inducible autoregulatory pathway. Science. 1993;259(5103):1912–5.PubMedCrossRefGoogle Scholar
  27. 27.
    Tran-Thi TA, Decker K, Baeuerle PA. Differential activation of transcription factors NF-kappa B and AP-1 in rat liver macrophages. Hepatology. 1995;22(2):613–9.PubMedCrossRefGoogle Scholar
  28. 28.
    Read MA et al. The proteasome pathway is required for cytokine-induced endothelial-leukocyte adhesion molecule expression. Immunity. 1995;2(5):493–506.PubMedCrossRefGoogle Scholar
  29. 29.
    Lakshminarayanan V, Drab-Weiss EA, Roebuck KA. H2O2 and tumor necrosis factor-alpha induce differential binding of the redox-responsive transcription factors AP-1 and NF-kappaB to the interleukin-8 promoter in endothelial and epithelial cells. J Biol Chem. 1998;273(49):32670–8.PubMedCrossRefGoogle Scholar
  30. 30.
    Teoh N et al. Dual role of tumor necrosis factor-alpha in hepatic ischemia-reperfusion injury: studies in tumor necrosis factor-alpha gene knockout mice. Hepatology. 2004;39(2):412–21.PubMedCrossRefGoogle Scholar
  31. 31.
    Luedde T et al. Deletion of IKK2 in hepatocytes does not sensitize these cells to TNF-induced apoptosis but protects from ischemia/reperfusion injury. J Clin Invest. 2005;115(4):849–59.PubMedGoogle Scholar
  32. 32.
    Beraza N et al. Hepatocyte-specific IKK gamma/NEMO expression determines the degree of liver injury. Gastroenterology. 2007;132(7):2504–17.PubMedCrossRefGoogle Scholar
  33. 33.
    Kuboki S et al. Hepatocyte NF-kappaB activation is hepatoprotective during ischemia-reperfusion injury and is augmented by ischemic hypothermia. Am J Physiol Gastrointest Liver Physiol. 2007;292(1):G201–7.PubMedCrossRefGoogle Scholar
  34. 34.
    Okaya T et al. Age-dependent responses to hepatic ischemia/reperfusion injury. Shock. 2005;24(5):421–7.PubMedCrossRefGoogle Scholar
  35. 35.
    Huber N et al. Age-related decrease in proteasome expression contributes to defective nuclear factor-kappaB activation during hepatic ischemia/reperfusion. Hepatology. 2009;49(5):1718–28.PubMedCrossRefGoogle Scholar
  36. 36.
    Llacuna L et al. Reactive oxygen species mediate liver injury through parenchymal nuclear factor-kappa B inactivation in prolonged ischemia/reperfusion. Am J Pathol. 2009;174(5):1776–85.PubMedCrossRefGoogle Scholar
  37. 37.
    Marden JJ et al. JunD protects the liver from ischemia/reperfusion injury by dampening AP-1 transcriptional activation. J Biol Chem. 2008;283(11):6687–95.PubMedCrossRefGoogle Scholar
  38. 38.
    Uehara T et al. JNK mediates hepatic ischemia reperfusion injury. J Hepatol. 2005;42(6):850–9.PubMedCrossRefGoogle Scholar
  39. 39.
    Zhou W et al. Subcellular site of superoxide dismutase expression differentially controls AP-1 activity and injury in mouse liver following ischemia/reperfusion. Hepatology. 2001;33(4):902–14.PubMedCrossRefGoogle Scholar
  40. 40.
    Butler KL et al. STAT-3 activation is necessary for ischemic preconditioning in hypertrophied myocardium. Am J Physiol Heart Circ Physiol. 2006;291(2):H797–803.PubMedCrossRefGoogle Scholar
  41. 41.
    Bolli R, Dawn B, Xuan YT. Role of the JAK-STAT pathway in protection against myocardial ischemia/reperfusion injury. Trends Cardiovasc Med. 2003;13(2):72–9.PubMedCrossRefGoogle Scholar
  42. 42.
    Matsumoto T et al. Interleukin-6 and STAT3 protect the liver from hepatic ischemia and reperfusion injury during ischemic preconditioning. Surgery. 2006;140(5):793–802.PubMedCrossRefGoogle Scholar
  43. 43.
    Lentsch AB et al. Requirement for interleukin-12 in the pathogenesis of warm hepatic ischemia/reperfusion injury in mice. Hepatology. 1999;30(6):1448–53.PubMedCrossRefGoogle Scholar
  44. 44.
    Kato A et al. Promotion of hepatic ischemia/reperfusion injury by IL-12 is independent of STAT4. Transplantation. 2002;73(7):1142–5.PubMedCrossRefGoogle Scholar
  45. 45.
    Shen XD et al. Stat4 and Stat6 signaling in hepatic ischemia/reperfusion injury in mice: HO-1 dependence of Stat4 disruption-mediated cytoprotection. Hepatology. 2003;37(2):296–303.PubMedCrossRefGoogle Scholar
  46. 46.
    Kato A et al. Regulation of liver inflammatory injury by signal transducer and activator of transcription-6. Am J Pathol. 2000;157(1):297–302.PubMedCrossRefGoogle Scholar
  47. 47.
    Evans RM. The steroid and thyroid hormone receptor superfamily. Science. 1988;240(4854):889–95.PubMedCrossRefGoogle Scholar
  48. 48.
    Mangelsdorf DJ et al. The nuclear receptor superfamily: the second decade. Cell. 1995;83(6):835–9.PubMedCrossRefGoogle Scholar
  49. 49.
    Jiang C, Ting AT, Seed B. PPAR-gamma agonists inhibit production of monocyte inflammatory cytokines. Nature. 1998;391(6662):82–6.PubMedCrossRefGoogle Scholar
  50. 50.
    von Knethen A, Brune B. PPARgamma – an important regulator of monocyte/macrophage function. Arch Immunol Ther Exp (Warsz). 2003;51(4):219–26.Google Scholar
  51. 51.
    Berger J et al. Thiazolidinediones produce a conformational change in peroxisomal proliferator-activated receptor-gamma: binding and activation correlate with antidiabetic actions in db/db mice. Endocrinology. 1996;137(10):4189–95.PubMedCrossRefGoogle Scholar
  52. 52.
    Reynaert H, Geerts A, Henrion J. Review article: the treatment of non-alcoholic steatohepatitis with thiazolidinediones. Aliment Pharmacol Ther. 2005;22(10):897–905.PubMedCrossRefGoogle Scholar
  53. 53.
    Shin T et al. Activation of peroxisome proliferator-activated receptor-gamma during hepatic ischemia is age-dependent. J Surg Res. 2008;147(2):200–5.PubMedCrossRefGoogle Scholar
  54. 54.
    Nakajima A et al. Endogenous PPAR gamma mediates anti-inflammatory activity in murine ischemia-reperfusion injury. Gastroenterology. 2001;120(2):460–9.PubMedCrossRefGoogle Scholar
  55. 55.
    Sivarajah A et al. Agonists of peroxisome-proliferator activated receptor-gamma reduce renal ischemia/reperfusion injury. Am J Nephrol. 2003;23(4):267–76.PubMedCrossRefGoogle Scholar
  56. 56.
    Okada M, Yan SF, Pinsky DJ. Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) activation suppresses ischemic induction of Egr-1 and its inflammatory gene targets. FASEB J. 2002;16(14):1861–8.PubMedCrossRefGoogle Scholar
  57. 57.
    Al-Rasheed NM et al. Ligand-independent activation of peroxisome proliferator-activated receptor-gamma by insulin and C-peptide in kidney proximal tubular cells: dependent on phosphatidylinositol 3-kinase activity. J Biol Chem. 2004;279(48):49747–54.PubMedCrossRefGoogle Scholar
  58. 58.
    Wahren J et al. Role of C-peptide in human physiology. Am J Physiol Endocrinol Metab. 2000;278(5):E759–68.PubMedGoogle Scholar
  59. 59.
    Kuboki S et al. Peroxisome proliferator-activated receptor-gamma protects against hepatic ischemia/reperfusion injury in mice. Hepatology. 2008;47(1):215–24.PubMedCrossRefGoogle Scholar
  60. 60.
    Clark RB. The role of PPARs in inflammation and immunity. J Leukoc Biol. 2002;71(3):388–400.PubMedGoogle Scholar
  61. 61.
    Daynes RA, Jones DC. Emerging roles of PPARs in inflammation and immunity. Nat Rev Immunol. 2002;2(10):748–59.PubMedCrossRefGoogle Scholar
  62. 62.
    Braissant O et al. Differential expression of peroxisome proliferator-activated receptors (PPARs): tissue distribution of PPAR-alpha, -beta, and -gamma in the adult rat. Endocrinology. 1996;137(1):354–66.PubMedCrossRefGoogle Scholar
  63. 63.
    Peters JM et al. Peroxisome proliferator-activated receptor alpha is restricted to hepatic parenchymal cells, not Kupffer cells: implications for the mechanism of action of peroxisome proliferators in hepatocarcinogenesis. Carcinogenesis. 2000;21(4):823–6.PubMedCrossRefGoogle Scholar
  64. 64.
    Okaya T, Lentsch AB. Peroxisome proliferator-activated receptor-alpha regulates postischemic liver injury. Am J Physiol Gastrointest Liver Physiol. 2004;286(4):G606–12.PubMedCrossRefGoogle Scholar
  65. 65.
    Myers KJ et al. Interleukin-12-induced adhesion molecule expression in murine liver. Am J Pathol. 1998;152(2):457–68.PubMedGoogle Scholar
  66. 66.
    Zisman DA et al. Anti-interleukin-12 therapy protects mice in lethal endotoxemia but impairs bacterial clearance in murine Escherichia coli peritoneal sepsis. Shock. 1997;8(5):349–56.PubMedCrossRefGoogle Scholar
  67. 67.
    Matsushita T et al. IL-12 induces specific cytotoxicity against regenerating hepatocytes in vivo. Int Immunol. 1999;11(5):657–65.PubMedCrossRefGoogle Scholar
  68. 68.
    Colletti LM et al. Role of tumor necrosis factor-alpha in the pathophysiologic alterations after hepatic ischemia/reperfusion injury in the rat. J Clin Invest. 1990;85(6):1936–43.PubMedCrossRefGoogle Scholar
  69. 69.
    Jaeschke H. Mechanisms of reperfusion injury after warm ischemia of the liver. J Hepatobiliary Pancreat Surg. 1998;5(4):402–8.PubMedCrossRefGoogle Scholar
  70. 70.
    Beutler B, Cerami A. The endogenous mediator of endotoxic shock. Clin Res. 1987;35(3):192–7.PubMedGoogle Scholar
  71. 71.
    Witthaut R et al. Complement and tumor necrosis factor-alpha contribute to Mac-1 (CD11b/CD18) up-regulation and systemic neutrophil activation during endotoxemia in vivo. J Leukoc Biol. 1994;55(1):105–11.PubMedGoogle Scholar
  72. 72.
    Lentsch AB et al. Inflammatory mechanisms and therapeutic strategies for warm hepatic ischemia/reperfusion injury. Hepatology. 2000;32(2):169–73.PubMedCrossRefGoogle Scholar
  73. 73.
    Klebanoff SJ et al. Stimulation of neutrophils by tumor necrosis factor. J Immunol. 1986;136(11):4220–5.PubMedGoogle Scholar
  74. 74.
    Shalaby MR et al. Activation of human polymorphonuclear neutrophil functions by interferon-gamma and tumor necrosis factors. J Immunol. 1985;135(3):2069–73.PubMedGoogle Scholar
  75. 75.
    Suzuki S, Toledo-Pereyra LH. Interleukin 1 and tumor necrosis factor production as the initial stimulants of liver ischemia and reperfusion injury. J Surg Res. 1994;57(2):253–8.PubMedCrossRefGoogle Scholar
  76. 76.
    Lentsch AB et al. Chemokine involvement in hepatic ischemia/reperfusion injury in mice: roles for macrophage inflammatory protein-2 and KC. Hepatology. 1998;27(4):1172–7.PubMedCrossRefGoogle Scholar
  77. 77.
    Rollins BJ. Chemokines. Blood. 1997;90(3):909–28.PubMedGoogle Scholar
  78. 78.
    Mantovani A, Bonecchi R, Locati M. Tuning inflammation and immunity by chemokine sequestration: decoys and more. Nat Rev Immunol. 2006;6(12):907–18.PubMedCrossRefGoogle Scholar
  79. 79.
    Murphy PM. International Union of Pharmacology: XXX. Update on chemokine receptor nomenclature. Pharmacol Rev. 2002;54(2):227–9.PubMedCrossRefGoogle Scholar
  80. 80.
    Behrends M et al. Remote renal injury following partial hepatic ischemia/reperfusion injury in rats. J Gastrointest Surg. 2008;12(3):490–5.PubMedCrossRefGoogle Scholar
  81. 81.
    Wanner GA et al. Liver ischemia and reperfusion induces a systemic inflammatory response through Kupffer cell activation. Shock. 1996;5(1):34–40.PubMedCrossRefGoogle Scholar
  82. 82.
    Braquet P et al. Perspectives in platelet-activating factor research. Pharmacol Rev. 1987;39(2):97–145.PubMedGoogle Scholar
  83. 83.
    Read RA et al. Platelet-activating factor-induced polymorpho-nuclear neutrophil priming independent of CD11b adhesion. Surgery. 1993;114(2):308–13.PubMedGoogle Scholar
  84. 84.
    Dubois C, Bissonnette E, Rola-Pleszczynski M. Platelet-activating factor (PAF) enhances tumor necrosis factor production by alveolar macrophages. Prevention by PAF receptor antagonists and lipoxygenase inhibitors. J Immunol. 1989;143(3):964–70.PubMedGoogle Scholar
  85. 85.
    Ruis NM, Rose JK, Valone FH. Tumor necrosis factor release by human monocytes stimulated with platelet-activating factor. Lipids. 1991;26(12):1060–4.PubMedCrossRefGoogle Scholar
  86. 86.
    Kuipers B et al. Platelet-activating factor antagonist TCV-309 attenuates the induction of the cytokine network in experimental endotoxemia in chimpanzees. J Immunol. 1994;152(5):2438–46.PubMedGoogle Scholar
  87. 87.
    Serizawa A et al. Involvement of platelet-activating factor in cytokine production and neutrophil activation after hepatic ischemia-reperfusion. Hepatology. 1996;23(6):1656–63.PubMedCrossRefGoogle Scholar
  88. 88.
    Yamakawa Y et al. Interaction of platelet activating factor, reactive oxygen species generated by xanthine oxidase, and leukocytes in the generation of hepatic injury after shock/resuscitation. Ann Surg. 2000;231(3):387–98.PubMedCrossRefGoogle Scholar
  89. 89.
    Minor T, Isselhard W. Platelet-activating factor antagonism enhances the liver’s recovery from warm ischemia in situ. J Hepatol. 1993;18(3):365–8.PubMedCrossRefGoogle Scholar
  90. 90.
    Akira S, Sato S. Toll-like receptors and their signaling mechanisms. Scand J Infect Dis. 2003;35(9):555–62.PubMedCrossRefGoogle Scholar
  91. 91.
    Iwasaki A, Medzhitov R. Toll-like receptor control of the adaptive immune responses. Nat Immunol. 2004;5(10):987–95.PubMedCrossRefGoogle Scholar
  92. 92.
    Medzhitov R. Toll-like receptors and innate immunity. Nat Rev Immunol. 2001;1(2):135–45.PubMedCrossRefGoogle Scholar
  93. 93.
    Vardanian AJ, Busuttil RW, Kupiec-Weglinski JW. Molecular mediators of liver ischemia and reperfusion injury: a brief review. Mol Med. 2008;14(5–6):337–45.PubMedGoogle Scholar
  94. 94.
    Takeuchi O et al. Differential roles of TLR2 and TLR4 in recognition of gram-negative and gram-positive bacterial cell wall components. Immunity. 1999;11(4):443–51.PubMedCrossRefGoogle Scholar
  95. 95.
    Horng T et al. The adaptor molecule TIRAP provides signalling specificity for Toll-like receptors. Nature. 2002;420(6913):329–33.PubMedCrossRefGoogle Scholar
  96. 96.
    Wang L, Xu JB, Wu HS, Zhang JX, Zhang JH, Tian Y, et al. The relationship between activation of TLR4 and partial hepatic ischemia/reperfusion injury in mice. Hepatobiliary Pancreat Dis Int. 2006;5(1):101–4.PubMedGoogle Scholar
  97. 97.
    Wang L et al. The relationship between activation of TLR4 and partial hepatic ischemia/reperfusion injury in mice. Hepatobiliary Pancreat Dis Int. 2006;5(1):101–4.PubMedGoogle Scholar
  98. 98.
    Wu HS et al. Toll-like receptor 4 involvement in hepatic ischemia/reperfusion injury in mice. Hepatobiliary Pancreat Dis Int. 2004;3(2):250–3.PubMedGoogle Scholar
  99. 99.
    Castell JV et al. Plasma clearance, organ distribution and target cells of interleukin-6/hepatocyte-stimulating factor in the rat. Eur J Biochem. 1988;177(2):357–61.PubMedCrossRefGoogle Scholar
  100. 100.
    Camargo Jr CA et al. Interleukin-6 protects liver against warm ischemia/reperfusion injury and promotes hepatocyte proliferation in the rodent. Hepatology. 1997;26(6):1513–20.PubMedCrossRefGoogle Scholar
  101. 101.
    Heinrich PC et al. Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway. Biochem J. 1998;334(Pt 2):297–314.PubMedGoogle Scholar
  102. 102.
    Haga S et al. Stat3 protects against Fas-induced liver injury by redox-dependent and -independent mechanisms. J Clin Invest. 2003;112(7):989–98.PubMedGoogle Scholar
  103. 103.
    Ward PA, Lentsch AB. Endogenous regulation of the acute inflammatory response. Mol Cell Biochem. 2002;234–235(1–2):225–8.PubMedCrossRefGoogle Scholar
  104. 104.
    Lentsch AB et al. Secretory leukocyte protease inhibitor in mice regulates local and remote organ inflammatory injury induced by hepatic ischemia/reperfusion. Gastroenterology. 1999;117(4):953–61.PubMedCrossRefGoogle Scholar
  105. 105.
    Grobmyer SR et al. Secretory leukocyte protease inhibitor, an inhibitor of neutrophil activation, is elevated in serum in human sepsis and experimental endotoxemia. Crit Care Med. 2000;28(5):1276–82.PubMedCrossRefGoogle Scholar
  106. 106.
    Maines MD. The heme oxygenase system: a regulator of second messenger gases. Annu Rev Pharmacol Toxicol. 1997;37:517–54.PubMedCrossRefGoogle Scholar
  107. 107.
    Kato H et al. Heme oxygenase-1 overexpression protects rat livers from ischemia/reperfusion injury with extended cold preservation. Am J Transplant. 2001;1(2):121–8.PubMedCrossRefGoogle Scholar
  108. 108.
    Schmidt R et al. Heme oxygenase-1 induction by the clinically used anesthetic isoflurane protects rat livers from ischemia/reperfusion injury. Ann Surg. 2007;245(6):931–42.PubMedCrossRefGoogle Scholar
  109. 109.
    Tsuchihashi S et al. Basal rather than induced heme oxygenase-1 levels are crucial in the antioxidant cytoprotection. J Immunol. 2006;177(7):4749–57.PubMedGoogle Scholar
  110. 110.
    Fondevila C et al. Biliverdin therapy protects rat livers from ischemia and reperfusion injury. Hepatology. 2004;40(6):1333–41.PubMedCrossRefGoogle Scholar
  111. 111.
    Fondevila C et al. Biliverdin protects rat livers from ischemia/reperfusion injury. Transplant Proc. 2003;35(5):1798–9.PubMedCrossRefGoogle Scholar
  112. 112.
    Kaizu T et al. Carbon monoxide inhalation ameliorates cold ischemia/reperfusion injury after rat liver transplantation. Surgery. 2005;138(2):229–35.PubMedCrossRefGoogle Scholar
  113. 113.
    Hines IN et al. Endothelial nitric oxide synthase protects the post-ischemic liver: potential interactions with superoxide. Biomed Pharmacother. 2005;59(4):183–9.PubMedCrossRefGoogle Scholar
  114. 114.
    Varadarajan R et al. Nitric oxide in early ischaemia reperfusion injury during human orthotopic liver transplantation. Transplantation. 2004;78(2):250–6.PubMedCrossRefGoogle Scholar
  115. 115.
    Szabo C, Ischiropoulos H, Radi R. Peroxynitrite: biochemistry, pathophysiology and development of therapeutics. Nat Rev Drug Discov. 2007;6(8):662–80.PubMedCrossRefGoogle Scholar
  116. 116.
    Hamada T et al. Inducible nitric oxide synthase deficiency impairs matrix metalloproteinase-9 activity and disrupts leukocyte migration in hepatic ischemia/reperfusion injury. Am J Pathol. 2009;174(6):2265–77.PubMedCrossRefGoogle Scholar
  117. 117.
    Lee VG et al. The roles of iNOS in liver ischemia-reperfusion injury. Shock. 2001;16(5):355–60.PubMedCrossRefGoogle Scholar
  118. 118.
    Racanelli V, Rehermann B. The liver as an immunological organ. Hepatology. 2006;43(2 Suppl 1):S54–62.PubMedCrossRefGoogle Scholar
  119. 119.
    Caldwell CC, Tschoep J, Lentsch AB. Lymphocyte function during hepatic ischemia/reperfusion injury. J Leukoc Biol. 2007;82(3):457–64.PubMedCrossRefGoogle Scholar
  120. 120.
    Caldwell CC et al. Divergent functions of CD4+ T lymph-ocytes in acute liver inflammation and injury after ischemia-reperfusion. Am J Physiol Gastrointest Liver Physiol. 2005;289(5):G969–76.PubMedCrossRefGoogle Scholar
  121. 121.
    Zwacka RM et al. CD4(+) T-lymphocytes mediate ischemia/reperfusion-induced inflammatory responses in mouse liver. J Clin Invest. 1997;100(2):279–89.PubMedCrossRefGoogle Scholar
  122. 122.
    Bacon KB et al. Activation of dual T cell signaling pathways by the chemokine RANTES. Science. 1995;269(5231):1727–30.PubMedCrossRefGoogle Scholar
  123. 123.
    Anselmo DM et al. FTY720 pretreatment reduces warm hepatic ischemia reperfusion injury through inhibition of T-lymphocyte infiltration. Am J Transplant. 2002;2(9):843–9.PubMedCrossRefGoogle Scholar
  124. 124.
    Jaeschke H. Reactive oxygen and ischemia/reperfusion injury of the liver. Chem Biol Interact. 1991;79(2):115–36.PubMedCrossRefGoogle Scholar
  125. 125.
    Singh I et al. Role of P-selectin expression in hepatic ischemia and reperfusion injury. Clin Transplant. 1999;13(1 Pt 2):76–82.PubMedCrossRefGoogle Scholar
  126. 126.
    Sawaya Jr DE et al. P-selectin contributes to the initial recruitment of rolling and adherent leukocytes in hepatic venules after ischemia/reperfusion. Shock. 1999;12(3):227–32.PubMedCrossRefGoogle Scholar
  127. 127.
    Yadav SS et al. P-Selectin mediates reperfusion injury through neutrophil and platelet sequestration in the warm ischemic mouse liver. Hepatology. 1999;29(5):1494–502.PubMedCrossRefGoogle Scholar
  128. 128.
    Yadav SS et al. L-selectin and ICAM-1 mediate reperfusion injury and neutrophil adhesion in the warm ischemic mouse liver. Am J Physiol. 1998;275(6 Pt 1):G1341–52.PubMedGoogle Scholar
  129. 129.
    Farhood A et al. Intercellular adhesion molecule 1 (ICAM-1) expression and its role in neutrophil-induced ischemia-reperfusion injury in rat liver. J Leukoc Biol. 1995;57(3):368–74.PubMedGoogle Scholar
  130. 130.
    Kato A, Okaya T, Lentsch AB. Endogenous IL-13 protects hepatocytes and vascular endothelial cells during ischemia/reperfusion injury. Hepatology. 2003;37(2):304–12.PubMedCrossRefGoogle Scholar
  131. 131.
    Wu TW et al. Trolox protects rat hepatocytes against oxyradical damage and the ischemic rat liver from reperfusion injury. Hepatology. 1991;13(3):575–80.PubMedCrossRefGoogle Scholar
  132. 132.
    Bilzer M, Lauterburg BH. Effects of hypochlorous acid and chloramines on vascular resistance, cell integrity, and biliary glutathione disulfide in the perfused rat liver: modulation by glutathione. J Hepatol. 1991;13(1):84–9.PubMedCrossRefGoogle Scholar
  133. 133.
    Mavier P et al. In vitro toxicity of polymorphonuclear neutrophils to rat hepatocytes: evidence for a proteinase-mediated mechanism. Hepatology. 1988;8(2):254–8.PubMedCrossRefGoogle Scholar
  134. 134.
    Hamada T et al. Metalloproteinase-9 deficiency protects against hepatic ischemia/reperfusion injury. Hepatology. 2008;47(1):186–98.PubMedCrossRefGoogle Scholar
  135. 135.
    Weiss SJ. Tissue destruction by neutrophils. N Engl J Med. 1989;320(6):365–76.PubMedCrossRefGoogle Scholar
  136. 136.
    Barone S et al. Distinct and sequential upregulation of genes regulating cell growth and cell cycle progression during hepatic ischemia-reperfusion injury. Am J Physiol Cell Physiol. 2005;289(4):C826–35.PubMedCrossRefGoogle Scholar
  137. 137.
    Kuribayashi K, El-Deiry WS. Regulation of programmed cell death by the p53 pathway. Adv Exp Med Biol. 2008;615:201–21.PubMedCrossRefGoogle Scholar
  138. 138.
    Lohr K et al. p21/CDKN1A mediates negative regulation of transcription by p53. J Biol Chem. 2003;278(35):32507–16.PubMedCrossRefGoogle Scholar
  139. 139.
    Strieter RM et al. CXC chemokines in angiogenesis. Cytokine Growth Factor Rev. 2005;16(6):593–609.PubMedCrossRefGoogle Scholar
  140. 140.
    Strieter RM et al. The functional role of the ELR motif in CXC chemokine-mediated angiogenesis. J Biol Chem. 1995;270(45):27348–57.PubMedCrossRefGoogle Scholar
  141. 141.
    Bone-Larson CL et al. IFN-gamma-inducible protein-10 (CXCL10) is hepatoprotective during acute liver injury through the induction of CXCR2 on hepatocytes. J Immunol. 2001;167(12):7077–83.PubMedGoogle Scholar
  142. 142.
    Colletti LM et al. Proliferative effects of CXC chemokines in rat hepatocytes in vitro and in vivo. Shock. 1998;10(4):248–57.PubMedCrossRefGoogle Scholar
  143. 143.
    Ren X et al. Mitogenic properties of endogenous and pharmacological doses of macrophage inflammatory protein-2 after 70% hepatectomy in the mouse. Am J Pathol. 2003;163(2):563–70.PubMedCrossRefGoogle Scholar
  144. 144.
    Kuboki S et al. Hepatocyte signaling through CXC chemokine receptor-2 is detrimental to liver recovery after ischemia/reperfusion in mice. Hepatology. 2008;48(4):1213–23.PubMedCrossRefGoogle Scholar
  145. 145.
    Stefanovic L, Brenner DA, Stefanovic B. Direct hepatotoxic effect of KC chemokine in the liver without infiltration of neutrophils. Exp Biol Med (Maywood). 2005;230(8):573–86.Google Scholar
  146. 146.
    Raffucci FL, Lewis FJ, Wangensteen OH. Hypothermia in experimental hepatic surgery. Proc Soc Exp Biol Med. 1953;83(3):639–40.PubMedGoogle Scholar
  147. 147.
    Kato A et al. Mechanisms of hypothermic protection against ischemic liver injury in mice. Am J Physiol Gastrointest Liver Physiol. 2002;282(4):G608–16.PubMedGoogle Scholar
  148. 148.
    Yamanaka N, Dai CL, Okamoto E. Historical evolution of hypothermic liver surgery. World J Surg. 1998;22(10):1104–7.PubMedCrossRefGoogle Scholar
  149. 149.
    Lemasters JJ, Thurman RG. Reperfusion injury after liver preservation for transplantation. Annu Rev Pharmacol Toxicol. 1997;37:327–38.PubMedCrossRefGoogle Scholar
  150. 150.
    Meng Q. Hypothermic preservation of hepatocytes. Biotechnol Prog. 2003;19(4):1118–27.PubMedCrossRefGoogle Scholar
  151. 151.
    Rai R et al. The use of isosafe verifiable temperature control unit for liver graft storage prior to orthotopic liver transplantation. Transplant Proc. 2003;35(2):771–2.PubMedCrossRefGoogle Scholar
  152. 152.
    Hertl M et al. The effects of hepatic preservation at 0 degrees C compared to 5 degrees C: influence of antiproteases and periodic flushing. Cryobiology. 1994;31(5):434–40.PubMedCrossRefGoogle Scholar
  153. 153.
    Kerkweg U et al. Cold-induced apoptosis of rat liver endothelial cells: contribution of mitochondrial alterations. Transplantation. 2003;76(3):501–8.PubMedCrossRefGoogle Scholar
  154. 154.
    Kang KJ. Mechanism of hepatic ischemia/reperfusion injury and protection against reperfusion injury. Transplant Proc. 2002;34(7):2659–61.PubMedCrossRefGoogle Scholar
  155. 155.
    Cywes R et al. Prediction of the outcome of transplantation in man by platelet adherence in donor liver allografts. Evidence of the importance of prepreservation injury. Transplantation. 1993;56(2):316–23.PubMedCrossRefGoogle Scholar
  156. 156.
    Cywes R et al. Role of platelets in hepatic allograft preservation injury in the rat. Hepatology. 1993;18(3):635–47.PubMedCrossRefGoogle Scholar
  157. 157.
    Sindram D et al. Platelets induce sinusoidal endothelial cell apoptosis upon reperfusion of the cold ischemic rat liver. Gastroenterology. 2000;118(1):183–91.PubMedCrossRefGoogle Scholar
  158. 158.
    Upadhya GA, Strasberg SM. Platelet adherence to isolated rat hepatic sinusoidal endothelial cells after cold preservation. Transplantation. 2002;73(11):1764–70.PubMedCrossRefGoogle Scholar
  159. 159.
    Selzner N et al. Cold ischemia decreases liver regeneration after partial liver transplantation in the rat: A TNF-alpha/IL-6-dependent mechanism. Hepatology. 2002;36(4 Pt 1):812–8.PubMedGoogle Scholar
  160. 160.
    Shin T, Kuboki S, Lentsch AB. Role of nuclear factor-κ(kappa)B in postischemic liver. Hepatol Res. 2008;38:429–40.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Callisia N. Clarke
  • Amit D. Tevar
  • Alex B. Lentsch
    • 1
  1. 1.Department of SurgeryUniversity of Cincinnati College of MedicineCincinnatiUSA

Personalised recommendations