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Molecular Medicine

, Volume 14, Issue 5–6, pp 337–345 | Cite as

Molecular Mediators of Liver Ischemia and Reperfusion Injury: A Brief Review

  • Andrew J. Vardanian
  • Ronald W. Busuttil
  • Jerzy W. Kupiec-Weglinski
Review Article

Abstract

Ischemia and reperfusion injury is a dynamic process that involves multiple organ systems in various clinical states including transplantation, trauma, and surgery. Research into this field has identified key molecular and signaling players that mediate, modulate, or augment cellular, tissue, and organ injury during this disease process. Further elucidation of the molecular mechanisms should provide the rationale to identify much-needed novel therapeutic options to prevent or ameliorate organ damage due to ischemia and reperfusion in clinics.

References

  1. 1.
    Yellon DM, Hausenloy DJ. (2007) Myocardial reperfusion injury. N. Engl. J. Med. 357:1121–35.CrossRefPubMedGoogle Scholar
  2. 2.
    Land W, et al. (1994) The beneficial effect of human recombinant superoxide dismutase on acute and chronic rejection events in recipients of cadaveric renal transplants. Transplantation 57:211–7.CrossRefPubMedGoogle Scholar
  3. 3.
    Land WG. (2005) The role of postischemic reperfusion injury and other nonantigen-dependent inflammatory pathways in transplantation. Transplantation 79:505–14.CrossRefPubMedGoogle Scholar
  4. 4.
    Fondevila C, Busuttil RW, Kupiec-Weglinski JW. (2003) Hepatic ischemia/reperfusion injury: a fresh look. Exp. Mol. Pathol. 74:86–93.CrossRefPubMedGoogle Scholar
  5. 5.
    Lemasters JJ, Nieminen AL, Qian T, Trost LC, Herman B. (1997) The mitochondrial permeability transition in toxic, hypoxic and reperfusion injury. Mol. Cell. Biochem. 174:159–65.CrossRefPubMedGoogle Scholar
  6. 6.
    Belzer FO, Southard JH. (1988) Principles of solid-organ preservation by cold storage. Transplantation 45:673–6.CrossRefPubMedGoogle Scholar
  7. 7.
    Takeda K, Kaisho T, Akira S. (2003) Toll-like receptors. Ann. Rev. Immunol. 21:335–76.CrossRefGoogle Scholar
  8. 8.
    Hopkins PA, Sriskandan S. (2005) Mammalian Toll-like receptors: to immunity and beyond. Clin. Exp. Immunol. 140:395–407.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Tsan MF, Gao B. (2004) Endogenous ligands of Toll-like receptors. J. Leukocyte Biol. 76:514–9.CrossRefPubMedGoogle Scholar
  10. 10.
    Foell D, Wittkowski H, Roth J. (2007) Mechanisms of disease: a ‘DAMP’ view of inflammatory arthritis. Nat. Clin. Pract. Rheumatol. 3:382–90.CrossRefPubMedGoogle Scholar
  11. 11.
    Roelofs MF, et al. (2006) Identification of small heat shock protein B8 (HSP22) as a novel TLR4 ligand and potential involvement in the pathogenesis of rheumatoid arthritis. J. Immunol. 176:7021–7.CrossRefPubMedGoogle Scholar
  12. 12.
    Ohashi K, Burkart V, Flohe S, Kolb H. (2000) Cutting edge: heat shock protein 60 is a putative endogenous ligand of the toll-like receptor-4 complex. J. Immunol. 164:558–61.CrossRefPubMedGoogle Scholar
  13. 13.
    Levy RM, et al. (2007) Systemic inflammation and remote organ injury following trauma require HMGB1. Am. J. Physiol. Regul. Integr. Comp. Physiol. 293:R1538–44.CrossRefPubMedGoogle Scholar
  14. 14.
    Figueiredo RT, et al. (2007) Characterization of heme as activator of Toll-like receptor 4. J. Biol. Chem. 282:20221–9.CrossRefPubMedGoogle Scholar
  15. 15.
    Zhai Y, Qiao B SH, Gao F, Busuttil RW, Cheng G, Platt JL, Volk HD, Kupiec-Weglinski JW. Evidence for the pivotal role of endogenous TLR4 ligands in liver ischemia and reperfusion injury. Transplantation (In Press).Google Scholar
  16. 16.
    Zhai Y, et al. (2004) Cutting edge: TLR4 activation mediates liver ischemia/reperfusion inflammatory response via IFN regulatory factor 3-dependent MyD88-independent pathway. J. Immunol. 173:7115–9.CrossRefPubMedGoogle Scholar
  17. 17.
    Tsung A, et al. (2005) Hepatic ischemia/reperfusion injury involves functional TLR4 signaling in non-parenchymal cells. J. Immunol. 175:7661–8.CrossRefPubMedGoogle Scholar
  18. 18.
    Aprahamian CJ, Lorenz RG, Harmon CM, Dimmit RA. (2008) Toll-like receptor 2 is protective of ischemia-reperfusion-mediated small-bowel injury in a murine model. Pediatr. Crit. Care Med. 9:105–9.CrossRefPubMedGoogle Scholar
  19. 19.
    Leemans JC, et al. (2005) Renal-associated TLR2 mediates ischemia/reperfusion injury in the kidney. J. Clin. Invest. 115:2894–903.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Shigeoka AA, et al. (2007) TLR2 is constitutively expressed within the kidney and participates in ischemic renal injury through both MyD88-dependent and -independent pathways. J. Immunol. 178:6252–8.CrossRefPubMedGoogle Scholar
  21. 21.
    Wu H, et al. (2007) TLR4 activation mediates kidney ischemia/reperfusion injury. J. Clin. Invest. 117:2847–59.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Oyama J, et al. (2004) Reduced myocardial ischemia-reperfusion injury in toll-like receptor 4-deficient mice. Circulation 109:784–9.CrossRefPubMedGoogle Scholar
  23. 23.
    Kim SC, et al. (2007) Toll-like receptor 4 deficiency: smaller infarcts, but no gain in function. BMC Physiol. 7:5.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Hua F, et al. (2007) Protection against myocardial ischemia/reperfusion injury in TLR4-deficient mice is mediated through a phosphoinositide 3-kinase-dependent mechanism. J. Immunol. 178:7317–24.CrossRefPubMedGoogle Scholar
  25. 25.
    Hua F, et al. (2005) Blocking the MyD88-dependent pathway protects the myocardium from ischemia/reperfusion injury in rat hearts. Biochem. Biophys. Res. Commun. 338:1118–25.CrossRefPubMedGoogle Scholar
  26. 26.
    Jaeschke H, Farhood A. (1991) Neutrophil and Kupffer cell-induced oxidant stress and ischemia-reperfusion injury in rat liver. Am. J. Physiol. 260:G355–62.CrossRefPubMedGoogle Scholar
  27. 27.
    Jaeschke H, Smith CW, Clemens MG, Ganey PE, Roth RA. (1996) Mechanisms of inflammatory liver injury: adhesion molecules and cytotoxicity of neutrophils. Toxicol. Appl. Pharmacol. 139:213–26.CrossRefPubMedGoogle Scholar
  28. 28.
    Jaeschke H. (2002) Reperfusion injury after warm ischemia or cold storage of the liver: role of apoptotic cell death. Transplant. Proc. 34:2656–8.CrossRefPubMedGoogle Scholar
  29. 29.
    Poli G, Cutrin JC, Biasi F. (1998) Lipid peroxidation in the reperfusion injury of the liver. Free Radic. Res. 28:547–51.CrossRefPubMedGoogle Scholar
  30. 30.
    Jaeschke H. (2000) Reactive oxygen and mechanisms of inflammatory liver injury. J. Gastroenterol. Hepatol. 15:718–24.CrossRefPubMedGoogle Scholar
  31. 31.
    Szabo C, Ischiropoulos H, Radi R. (2007) Peroxynitrite: biochemistry, pathophysiology and development of therapeutics. Nat. Rev. Drug Discov. 6:662–80.CrossRefPubMedGoogle Scholar
  32. 32.
    Yuzawa H, et al. (2005) Inhibitory effects of safe and novel SOD derivatives, galactosylated-SOD, on hepatic warm ischemia/reperfusion injury in pigs. Hepatogastroenterology 52:839–43.PubMedGoogle Scholar
  33. 33.
    Mizoe A, et al. (1997) Preventive effects of superoxide dismutase derivatives modified with monosaccharides on reperfusion injury in rat liver transplantation. J. Surg. Res. 73:160–5.CrossRefPubMedGoogle Scholar
  34. 34.
    Ejiri S, Eguchi Y, Kishida A, Kurumi Y, Tani T, Kodama M. (2000) Protective effect of OPC-6535, a superoxide anion production inhibitor, on liver grafts subjected to warm ischemia during porcine liver transplantation. Transplant Proc. 32:318–21.CrossRefPubMedGoogle Scholar
  35. 35.
    He SQ, et al. (2006) Delivery of antioxidative enzyme genes protects against ischemia/reperfusion-induced liver injury in mice. Liver Transpl. 12:1869–79.CrossRefPubMedGoogle Scholar
  36. 36.
    Lehmann TG, et al. (2000) Gene delivery of Cu/Zn-superoxide dismutase improves graft function after transplantation of fatty livers in the rat. Hepatology (Baltimore) 32:1255–64.CrossRefGoogle Scholar
  37. 37.
    Wu TJ, Khoo NH, Zhou F, Day BJ, Parks DA. (2007) Decreased hepatic ischemia-reperfusion injury by manganese-porphyrin complexes. Free Radic. Res. 41:127–34.CrossRefPubMedGoogle Scholar
  38. 38.
    Dulundu E, et al. (2007) Alpha-lipoic acid protects against hepatic ischemia-reperfusion injury in rats. Pharmacology 79:163–70.CrossRefPubMedGoogle Scholar
  39. 39.
    Abe T, et al. (2004) A new free radical scavenger, edaravone, ameliorates oxidative liver damage due to ischemia-reperfusion in vitro and in vivo. J. Gastrointest. Surg. 8:604–15.CrossRefPubMedGoogle Scholar
  40. 40.
    Ninomiya M, Shimada M, Harada N, Soejima Y, Suehiro T, Maehara Y. (2004) The hydroxyl radical scavenger MCI-186 protects the liver from experimental cold ischaemia-reperfusion injury. Br. J. Surg. 91:184–90.CrossRefPubMedGoogle Scholar
  41. 41.
    Ninomiya M, et al. (2002) Beneficial effect of MCI-186 on hepatic warm ischemia-reperfusion in the rat. Transplantation 74:1470–2.CrossRefPubMedGoogle Scholar
  42. 42.
    Sepodes B, et al. (2004) Tempol, an intracellular free radical scavenger, reduces liver injury in hepatic ischemia-reperfusion in the rat. Transplant. Proc. 36:849–53.CrossRefPubMedGoogle Scholar
  43. 43.
    Yokota R, et al. (2000) A novel hydroxyl radical scavenger, nicaraven, protects the liver from warm ischemia and reperfusion injury. Surgery 127:661–9.CrossRefPubMedGoogle Scholar
  44. 44.
    Moncada S, Higgs A. (1993) The L-arginine-nitric oxide pathway. N. Engl. J. Med. 329:2002–12.CrossRefPubMedGoogle Scholar
  45. 45.
    Mocellin S, Bronte V, Nitti D. (2007) Nitric oxide, a double edged sword in cancer biology: searching for therapeutic opportunities. Med. Res. Rev. 27:317–52.CrossRefPubMedGoogle Scholar
  46. 46.
    Bogdan C. (2001) Nitric oxide and the immune response. Nat. Immunol. 2:907–16.CrossRefGoogle Scholar
  47. 47.
    Hara Y, Teramoto K, Ishidate K, Arii S. (2006) Cytoprotective function of tetrahydrobiopterin in rat liver ischemia/reperfusion injury. Surgery 139:377–84.CrossRefPubMedGoogle Scholar
  48. 48.
    Hara Y, et al. (2005) Beneficial effect of tetrahydrobiopterin on the survival of rats exposed to hepatic ischemia-reperfusion injury. Transplant. Proc. 37:442–4.CrossRefPubMedGoogle Scholar
  49. 49.
    Kaizu T, et al. (2006) Donor graft adenoviral iNOS gene transfer ameliorates rat liver transplant preservation injury and improves survival. Hepatology (Baltimore) 43:464–73.CrossRefGoogle Scholar
  50. 50.
    Hines IN, Harada H, Flores S, Gao B, McCord JM, Grisham MB. (2005) Endothelial nitric oxide synthase protects the post-ischemic liver: potential interactions with superoxide. Biomed. Pharmacother. 59:183–9.CrossRefPubMedGoogle Scholar
  51. 51.
    Varadarajan R, et al. (2004) Nitric oxide in early ischaemia reperfusion injury during human orthotopic liver transplantation. Transplantation 78:250–6.CrossRefPubMedGoogle Scholar
  52. 52.
    Theruvath TP, Zhong Z, Currin RT, Ramshesh VK, Lemasters JJ. (2006) Endothelial nitric oxide synthase protects transplanted mouse livers against storage/reperfusion injury: role of vasodilatory and innate immunity pathways. Transplant. Proc. 38:3351–7.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Duranski MR, Elrod JW, Calvert JW, Bryan NS, Feelisch M, Lefer DJ. (2006) Genetic overexpression of eNOS attenuates hepatic ischemia-reperfusion injury. Am. J. Physiol. Heart Circ. Physiol. 291:H2980–6.CrossRefPubMedGoogle Scholar
  54. 54.
    Schwentker A, Billiar TR. (2002) Inducible nitric oxide synthase: from cloning to therapeutic applications. World J. Surg. 26:772–8.CrossRefPubMedGoogle Scholar
  55. 55.
    Liu P, Xu B, Quilley J, Wong PY. (2000) Peroxynitrite attenuates hepatic ischemia-reperfusion injury. Am. J. Physiol. Cell Physiol. 279:C1970–7.CrossRefPubMedGoogle Scholar
  56. 56.
    Kimura H, et al. (2003) Role of inducible nitric oxide synthase in pig liver transplantation. J. Surg. Res. 111:28–37.CrossRefPubMedGoogle Scholar
  57. 57.
    Koeppel TA, et al. (2007) Enhanced iNOS gene expression in the steatotic rat liver after normothermic ischemia. Eur. Surg. Res. 39:303–11.CrossRefPubMedGoogle Scholar
  58. 58.
    Tsuchihashi S, et al. (2006) FK330, a novel inducible nitric oxide synthase inhibitor, prevents ischemia and reperfusion injury in rat liver transplantation. Am. J. Transplant. 6:2013–22.CrossRefPubMedGoogle Scholar
  59. 59.
    Meguro M, et al. (2002) A novel inhibitor of inducible nitric oxide synthase (ONO-1714) prevents critical warm ischemia-reperfusion injury in the pig liver. Transplantation 73:1439–46.CrossRefPubMedGoogle Scholar
  60. 60.
    Shiva S, et al. (2007) Nitrite augments tolerance to ischemia/reperfusion injury via the modulation of mitochondrial electron transfer. J. Exp. Med. 204:2089–102.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Yagnik GP, Takahashi Y, Tsoulfas G, Reid K, Murase N, Geller DA. (2002) Blockade of the l-arginine/NO synthase pathway worsens hepatic apoptosis and liver transplant preservation injury. Hepatology (Baltimore) 36:573–81.CrossRefGoogle Scholar
  62. 62.
    Geller DA, Chia SH, Takahashi Y, Yagnik GP, Tsoulfas G, Murase N. (2001) Protective role of the l-arginine-nitric oxide synthase pathway on preservation injury after rat liver transplantation. JPEN J. Parenter. Enteral Nutr. 25:142–7.CrossRefPubMedGoogle Scholar
  63. 63.
    Reid KM, et al. (2007) Liver I/R injury is improved by the arginase inhibitor, N(omega)-hydroxy-nor-L-arginine (nor-NOHA). Am. J. Physiol. 292:G512–7.Google Scholar
  64. 64.
    Maines MD. (1997) The heme oxygenase system: a regulator of second messenger gases. Annu. Rev. Pharmacol. Toxicol. 37:517–54.CrossRefPubMedGoogle Scholar
  65. 65.
    Amersi F, et al. (1999) Upregulation of heme oxygenase-1 protects genetically fat Zucker rat livers from ischemia/reperfusion injury. J. Clin. Invest. 104:1631–9.CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Kato H, et al. (2001) Heme oxygenase-1 overexpression protects rat livers from ischemia/reperfusion injury with extended cold preservation. Am. J. Transplant. 1:121–8.CrossRefPubMedGoogle Scholar
  67. 67.
    Tsuchihashi S, Zhai Y, Bo Q, Busuttil RW, Kupiec-Weglinski JW. (2007) Heme oxygenase-1 mediated cytoprotection against liver ischemia and reperfusion injury: inhibition of type-1 interferon signaling. Transplantation 83:1628–34.CrossRefPubMedGoogle Scholar
  68. 68.
    Coito AJ, et al. (2002) Heme oxygenase-1 gene transfer inhibits inducible nitric oxide synthase expression and protects genetically fat Zucker rat livers from ischemia-reperfusion injury. Transplantation 74:96–102.CrossRefPubMedGoogle Scholar
  69. 69.
    Ke B, et al. (2002) Heme oxygenase-1 gene transfer prevents CD95/FasL-mediated apoptosis and improves liver allograft survival via carbon monoxide signaling pathway. Transplant. Proc. 34:1465–6.CrossRefPubMedGoogle Scholar
  70. 70.
    Ke B, et al. (2002) Heme oxygenase 1 gene transfer prevents CD95/Fas ligand-mediated apoptosis and improves liver allograft survival via carbon monoxide signaling pathway. Hum. Gene Ther. 13:1189–99.CrossRefPubMedGoogle Scholar
  71. 71.
    Tsuchihashi S, Livhits M, Zhai Y, Busuttil RW, Araujo JA, Kupiec-Weglinski JW. (2006) Basal rather than induced heme oxygenase-1 levels are crucial in the antioxidant cytoprotection. J. Immunol. 177:4749–57.CrossRefPubMedGoogle Scholar
  72. 72.
    Schmidt R, et al. (2007) Heme oxygenase-1 induction by the clinically used anesthetic isoflurane protects rat livers from ischemia/reperfusion injury. Ann. Surg. 245:931–42.CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Fondevila C, et al. (2004) Biliverdin therapy protects rat livers from ischemia and reperfusion injury. Hepatology (Baltimore) 40:1333–41.CrossRefGoogle Scholar
  74. 74.
    Fondevila C, et al. (2003) Biliverdin protects rat livers from ischemia/reperfusion injury. Transplant. Proc. 35:1798–9.CrossRefPubMedGoogle Scholar
  75. 75.
    Kato Y, et al. (2003) Bilirubin rinse: a simple protectant against the rat liver graft injury mimicking heme oxygenase-1 preconditioning. Hepatology (Baltimore) 38:364–73.CrossRefGoogle Scholar
  76. 76.
    Tang LM, et al. (2007) Exogenous biliverdin ameliorates ischemia-reperfusion injury in small-for-size rat liver grafts. Transplant. Proc. 39:1338–44.CrossRefPubMedGoogle Scholar
  77. 77.
    Kaizu T, et al. (2005) Carbon monoxide inhalation ameliorates cold ischemia/reperfusion injury after rat liver transplantation. Surgery 138:229–35.CrossRefPubMedGoogle Scholar
  78. 78.
    Amersi F, et al. (2002) Ex vivo exposure to carbon monoxide prevents hepatic ischemia/reperfusion injury through p38 MAP kinase pathway. Hepatology (Baltimore) 35:815–23.CrossRefGoogle Scholar
  79. 79.
    Racanelli V, Rehermann B. (2006) The liver as an immunological organ. Hepatology (Baltimore) 43:S54–62.CrossRefGoogle Scholar
  80. 80.
    Caldwell CC, Tschoep J, Lentsch AB. (2007) Lymphocyte function during hepatic ischemia/reperfusion injury. J. Leukocyte Biol. 82:457–64.CrossRefPubMedGoogle Scholar
  81. 81.
    Huang Y, Rabb H, Womer KL. (2007) Ischemia-reperfusion and immediate T cell responses. Cell. Immunol. 248:4–11.CrossRefPubMedPubMedCentralGoogle Scholar
  82. 82.
    Vachino G, et al. (1995) P-selectin glycoprotein ligand-1 is the major counter-receptor for P-selectin on stimulated T cells and is widely distributed in non-functional form on many lymphocytic cells. J. Biol. Chem. 270:21966–74.CrossRefPubMedGoogle Scholar
  83. 83.
    Yadav SS, Howell DN, Steeber DA, Harland RC, Tedder TF, Clavien PA. (1999) P-Selectin mediates reperfusion injury through neutrophil and platelet sequestration in the warm ischemic mouse liver. Hepatology (Baltimore) 29:1494–502.CrossRefGoogle Scholar
  84. 84.
    Tsuchihashi S, et al. (2006) 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. 176:616–24.CrossRefPubMedGoogle Scholar
  85. 85.
    Amersi F, et al. (2002) 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. 2:600–8.CrossRefPubMedGoogle Scholar
  86. 86.
    Amersi F, et al. (2001) A novel iron chelator in combination with a P-selectin antagonist prevents ischemia/reperfusion injury in a rat liver model. Transplantation 71:112–8.CrossRefPubMedGoogle Scholar
  87. 87.
    Dulkanchainun TS, et al. (1998) Reduction of hepatic ischemia/reperfusion injury by a soluble P-selectin glycoprotein ligand-1. Ann. Surg. 227:832–40.CrossRefPubMedPubMedCentralGoogle Scholar
  88. 88.
    Fuller TF, Sattler B, Binder L, Vetterlein F, Ringe B, Lorf T. (2001) Reduction of severe ischemia/reperfusion injury in rat kidney grafts by a soluble P-selectin glycoprotein ligand. Transplantation 72:216–22.CrossRefPubMedGoogle Scholar
  89. 89.
    Singbartl K, Green SA, Ley K. (2000) Blocking P-selectin protects from ischemia/reperfusion-induced acute renal failure. FASEB J. 14:48–54.CrossRefPubMedGoogle Scholar
  90. 90.
    Farmer DG, et al. (2002) Improved survival through the reduction of ischemia-reperfusion injury after rat intestinal transplantation using selective P-selectin blockade with P-selectin glycoprotein ligand-Ig. Transplant. Proc. 34:985.CrossRefPubMedGoogle Scholar
  91. 91.
    Farmer DG, et al. (2005) Disruption of P-selectin signaling modulates cell trafficking and results in improved outcomes after mouse warm intestinal ischemia and reperfusion injury. Transplantation 80:828–35.CrossRefPubMedGoogle Scholar
  92. 92.
    Carmody IC, et al. (2004) P-selectin knockout mice have improved outcomes with both warm ischemia and small bowel transplantation. Transplant. Proc. 36:263–4.CrossRefPubMedGoogle Scholar
  93. 93.
    Ran S, Downes A, Thorpe PE. (2002) Increased exposure of anionic phospholipids on the surface of tumor blood vessels. Cancer Res. 62:6132–40.PubMedGoogle Scholar
  94. 94.
    Kuypers FA, Larkin SK, Emeis JJ, Allison AC. (2007) Interaction of an annexin V homodimer (Diannexin) with phosphatidylserine on cell surfaces and consequent antithrombotic activity. Thromb. Haemost. 97:478–86.CrossRefPubMedGoogle Scholar
  95. 95.
    Shen XD, et al. (2007) Diannexin, a novel annexin V homodimer, protects rat liver transplants against cold ischemia-reperfusion injury. Am. J. Transplant. 7:2463–71.CrossRefPubMedGoogle Scholar
  96. 96.
    Teoh NC, et al. (2007) Diannexin, a novel annexin V homodimer, provides prolonged protection against hepatic ischemia-reperfusion injury in mice. Gastroenterology 133:632–46.CrossRefPubMedGoogle Scholar
  97. 97.
    Moore C, Shen XD, Gao F, Busuttil RW, Coito AJ. (2007) Fibronectin-alpha4beta1 integrin interactions regulate metalloproteinase-9 expression in steatotic liver ischemia and reperfusion injury. Am. J. Pathol. 170:567–77.CrossRefPubMedPubMedCentralGoogle Scholar
  98. 98.
    Hamada T, Fondevila C, Busuttil RW, Coito AJ. (2008) Metalloproteinase-9 deficiency protects against hepatic ischemia/reperfusion injury. Hepatology (Baltimore) 47:186–98.CrossRefGoogle Scholar
  99. 99.
    Khandoga A, et al. (2006) Matrix metalloproteinase-9 promotes neutrophil and T cell recruitment and migration in the postischemic liver. J. Leukocyte Biol. 79:1295–305.CrossRefPubMedGoogle Scholar
  100. 100.
    Zwacka RM, Zhang Y, Halldorson J, Schlossberg H, Dudus L, Engelhardt JF. (1997) CD4+ T-lymphocytes mediate ischemia/reperfusion-induced inflammatory responses in mouse liver. J. Clin. Invest. 100:279–89.CrossRefPubMedPubMedCentralGoogle Scholar
  101. 101.
    Zhai Y, et al. (2006) CXCR3+CD4+T cells mediate innate immune function in the pathophysiology of liver ischemia/reperfusion injury. J. Immunol. 176:6313–22.CrossRefPubMedGoogle Scholar
  102. 102.
    Day YJ, Marshall MA, Huang L, McDuffie MJ, Okusa MD, Linden J. (2004) Protection from ischemic liver injury by activation of A2A adenosine receptors during reperfusion: inhibition of chemokine induction. Am. J. Physiol. 286:G285–93.Google Scholar
  103. 103.
    Colletti LM, Green ME, Burdick MD, Strieter RM. (2000) The ratio of ELR+ to ELR CXC chemokines affects the lung and liver injury following hepatic ischemia/ reperfusion in the rat. Hepatology (Baltimore) 31:435–45.CrossRefGoogle Scholar
  104. 104.
    Caldwell CC, Okaya T, Martignoni A, Husted T, Schuster R, Lentsch AB. (2005) Divergent functions of CD4+ T lymphocytes in acute liver inflammation and injury after ischemia-reperfusion. Am. J. Physiol. 289:G969–76.Google Scholar
  105. 105.
    Rabb H, et al. (2000) Pathophysiological role of T lymphocytes in renal ischemia-reperfusion injury in mice. Am. J. Physiol. Renal Physiol. 279:F525–31.CrossRefPubMedGoogle Scholar
  106. 106.
    Lang JD Jr, et al. (2007) Inhaled NO accelerates restoration of liver function in adults following orthotopic liver transplantation. J. Clin. Invest. 117:2583–91.CrossRefPubMedPubMedCentralGoogle Scholar
  107. 107.
    Baskin-Bey ES, et al. (2007) Clinical trial of the pan-caspase inhibitor, IDN-6556, in human liver preservation injury. Am. J. Transplant. 7:218–25.CrossRefPubMedGoogle Scholar
  108. 108.
    Aldrighetti L, et al. (2006) Impact of preoperative steroids administration on ischemia-reperfusion injury and systemic responses in liver surgery: a prospective randomized study. Liver Transpl. 12:941–9.CrossRefPubMedGoogle Scholar
  109. 109.
    Muratore A, Ribero D, Ferrero A, Bergero R, Capussotti L. (2003) Prospective randomized study of steroids in the prevention of ischaemic injury during hepatic resection with pedicle clamping. Br. J. Surg. 90:17–22.CrossRefPubMedGoogle Scholar
  110. 110.
    St Peter SD, Post DJ, Rodriguez-Davalos MI, Douglas DD, Moss AA, Mulligan DC. (2003) Tacrolimus as a liver flush solution to ameliorate the effects of ischemia/reperfusion injury following liver transplantation. Liver Transpl. 9:144–9.CrossRefPubMedGoogle Scholar
  111. 111.
    Khan AW, Fuller BJ, Shah SR, Davidson BR, Rolles K. (2005) A prospective randomized trial of N-acetyl cysteine administration during cold preservation of the donor liver for transplantation. Ann. Hepatol. 4:121–6.PubMedGoogle Scholar
  112. 112.
    Goggins WC, et al. (2003) A prospective, randomized, clinical trial of intraoperative versus postoperative Thymoglobulin in adult cadaveric renal transplant recipients. Transplantation 76:798–802.CrossRefPubMedGoogle Scholar
  113. 113.
    Bogetti D, et al. (2005) Thymoglobulin induction protects liver allografts from ischemia/reperfusion injury. Clin. Transplant. 19:507–11.CrossRefPubMedGoogle Scholar
  114. 114.
    Ito K, Ozasa H, Sanada K, Horikawa S. (2000) Doxorubicin preconditioning: a protection against rat hepatic ischemia-reperfusion injury. Hepatology (Baltimore) 31:416–9.CrossRefGoogle Scholar
  115. 115.
    Shen XD, et al. (2002) CD154-CD40 T-cell co-stimulation pathway is required in the mechanism of hepatic ischemia/reperfusion injury, and its blockade facilitates and depends on heme oxygenase-1 mediated cytoprotection. Transplantation 74:315–9.CrossRefPubMedGoogle Scholar
  116. 116.
    Redaelli CA, Tian YH, Schaffner T, Ledermann M, Baer HU, Dufour JF. (2002) Extended preservation of rat liver graft by induction of heme oxygenase-1. Hepatology (Baltimore) 35:1082–92.CrossRefGoogle Scholar
  117. 117.
    Berberat PO, et al. (2003) Heavy chain ferritin acts as an antiapoptotic gene that protects livers from ischemia reperfusion injury. FASEB J. 17:1724–6.CrossRefPubMedGoogle Scholar
  118. 118.
    Ke B, Shen XD, Lassman CR, Gao F, Busuttil RW, Kupiec-Weglinski JW. (2003) Cytoprotective and antiapoptotic effects of IL-13 in hepatic cold ischemia/reperfusion injury are heme oxygenase-1 dependent. Am. J. Transplant. 3:1076–82.CrossRefPubMedGoogle Scholar
  119. 119.
    Shen XD, et al. (2003) Stat4 and Stat6 signaling in hepatic ischemia/reperfusion injury in mice: HO-1 dependence of Stat4 disruption-mediated cytoprotection. Hepatology (Baltimore) 37:296–303.CrossRefGoogle Scholar
  120. 120.
    Ke B, et al. (2004) Gene therapy for liver transplantation using adenoviral vectors: CD40-CD154 blockade by gene transfer of CD40Ig protects rat livers from cold ischemia and reperfusion injury. Mol. Ther. 9:38–45.CrossRefPubMedPubMedCentralGoogle Scholar
  121. 121.
    Shen XD, et al. (2005) Toll-like receptor and heme oxygenase-1 signaling in hepatic ischemia/reperfusion injury. Am. J. Transplant. 5:1793–800.CrossRefPubMedGoogle Scholar
  122. 122.
    Kim YI, Hwang YJ, Song KE, Yun YK, Lee JW, Chun BY. (2002) Hepatocyte protection by a protease inhibitor against ischemia/reperfusion injury of human liver. J. Am. Coll. Surg. 195:41–50.CrossRefPubMedGoogle Scholar

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© Feinstein Institute for Medical Research 2008

Authors and Affiliations

  • Andrew J. Vardanian
    • 1
  • Ronald W. Busuttil
    • 1
  • Jerzy W. Kupiec-Weglinski
    • 1
  1. 1.Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at UCLAThe Dumont UCLA Transplantation CenterLos AngelesUSA

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