Research Advancement on Gene Therapy for Hepatic Ischemia-Reperfusion Injury_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

LIU Bing , QIN Huadong , WEI Guojun , SHI Tiefeng , SUN Yu

The 4th Department of General Surgery, The 2nd Affiliated Hospital of Harbin Medical University, Harbin 150086, ChinaCorresponding Author: QIN Hua-dong, E-mail: olwl@163.com;

Corresponding author：

Keywords：

Ischemia-reperfusion injury; Gene; Cell apoptosis; Genetic carrier

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Objective 　To summarize recent research advancement on gene therapy for hepatic ischemia-reperfusion injury (IRI). Methods 　Relevant references about basic and clinical researches of hepatic IRI were collected and reviewed.
Results 　Recent experimental researches indicated that the expression of several genes and cytokines could protect hepatic cells by suppressing cell apoptosis, decreasing the production of oxyradical, remaining and improving portal venous flow, promoting bilifaction, self immunoloregulation and decreasing inflammatory reaction, so that it could decrease IRI.
Conclusion 　IRI could be decreased by regulating the expressing of target genes or transducing relative genes in vivo, but the path of gene transfer and the selection and optimization of gene carrier still need more basic and clinical researches to prove.

Citation： LIU Bing,QIN Huadong,WEI Guojun,SHI Tiefeng,SUN Yu. Research Advancement on Gene Therapy for Hepatic Ischemia-Reperfusion Injury. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2009, 16(4): 336-339. doi: Copy

1.	Jennings ER, Hindmarsh C. Hemagglutination test for viral hepatitis with special reference to nonspecific reactions[Ｊ]. J Lab Clin Med, 1960; 55: 519-521.
2.	Suzuki F, Hashikura Y, Ise H, et al. MCI-186 (edaravone), a free radical scavenger, attenuates hepatic warm ischemia-reperfusion injury in rats [Ｊ]. Transpl Int, 2005; 18(7): 844-853.
3.	Nakatani K, Kaneda K, Seki S, et al. Pit cells as liver-associated natural killer cells: morphology and function [Ｊ]. Med Electron Microsc, 2004; 37(1): 29-36.
4.	Teoh N, Field J, Sutton J, et al. Dual role of tumor necrosis factor-alpha in hepatic ischemia-reperfusion injury: studies in tumor necrosis factor-alpha gene knockout mice [Ｊ]. Hepatology, 2004; 39(2): 412-421.
5.	Zhai Y, Shen XD, Hancock WW, et al. CXCR3+CD4+ T cells mediate innate immune function in the pathophysiology of liver ischemia/reperfusion injury [Ｊ]. J Immunol, 2006; 176(10): 6313-6322.〖ＪP〗.
6.	Fischer M, Harvima IT, Carvalho RF, et al. Mast cell CD30 ligand is upregulated in cutaneous inflammation and mediates degranulation-independent chemokine secretion [Ｊ]. J Clin Invest, 2006; 116(10): 2748-2756.
7.	Odashima M, Otaka M, Jin M, et al. Selective A2A adenosine agonist ATL-146e attenuates acute lethal liver injury in mice [Ｊ]. J Gastroenterol, 2005; 40(5): 526-529.
8.	Mizuguchi H, Hayakawa T. Targeted adenovirus vectors [Ｊ]. Hum Gene Ther, 2004; 15(11): 1034-1044.
9.	Savransky V, Molls RR, Burne-Taney M, et al. Role of the T-cell receptor in kidney ischemia-reperfusion injury [Ｊ]. Kidney Int, 2006; 69(2): 233-238.
10.	Ke B, Shen XD, Gao F, et al. Interleukin 13 gene transfer in liver ischemia and reperfusion injury: role of Stat6 and TLR4 pathways in cytoprotection [Ｊ]. Hum Gene Ther, 2004; 15(7): 691-698.
11.	Berberat PO, Katori M, Kaczmarek E, et al. Heavy chain ferritin acts as an antiapoptotic gene that protects livers from ischemia reperfusion injury [Ｊ]. FASEB J, 2003; 17(12): 1724-1726.
12.	Caldwell CC, Okaya T, Martignoni A, et al. Divergent functions of CD4+ T lymphocytes in acute liver inflammation and injury after ischemia-reperfusion [Ｊ]. Am J Physiol Gastrointest Liver Physiol, 2005; 289(5): G969-G976.
13.	Day YJ, Marshall MA, Huang L, et al. Protection from ischemic liver injury by activation of A2A adenosine receptors during reperfusion: inhibition of chemokine induction [Ｊ]. Am J Physiol Gastrointest Liver Physiol, 2004; 286(2): G285-G293.
14.	Zhang M, Alicot EM, Chiu I, et al. Identification of the target self-antigens in reperfusion injury [Ｊ]. J Exp Med, 2006; 203(1): 141-152.
15.	Gao W, Bentley RC, Madden JF, et al. Apoptosis of sinusoidal endothelial cells is a critical mechanism of preservation injury in rat liver transplantation [Ｊ]. Hepatology, 1998; 27(6): 1652-1660.
16.	Bilbao G, Contreras JL, Eckhoff DE, et al. Reduction of ischemia-reperfusion injury of the liver by in vivo adenovirus-mediated gene transfer of the antiapoptotic Bcl-2 gene [Ｊ]. Ann Surg, 1999; 230(2): 185-193.
17.	Barrier A, Olaya N, Chiappini F, et al. Ischemic preconditioning modulates the expression of several genes, leading to the overproduction of IL-1Ra, iNOS, and Bcl-2 in a human model of liver ischemia-reperfusion [Ｊ]. FASEB J, 2005; 19(12): 1617-1626.
18.	Ma W, Wang ZR, Shi L, et al. Expression of macrophage inflammatory protein-1 alpha in Kupffer cells following liver ischemia or reperfusion injury in rats [Ｊ]. World J Gastroenterol, 2006; 12(24): 3854-3858.
19.	Sawitzki B, Amersi F, Ritter T, et al. Upregulation of Bag-1 by ex vivo gene transfer protects rat livers from ischemia/reperfusion injury [Ｊ]. Hum Gene Ther, 2002; 13(12): 1495-1504.
20.	El-Ghoneimi A, Cursio R, Schmid-Alliana A, et al. Inhibition of tumor necrosis factor alpha gene transcription by pentoxifylline reduces normothermic liver ischemia-reperfusion injury in rats [Ｊ]. Transplant Proc, 2007; 39(6): 1761-1764.
21.	Ke B, Shen XD, Tsuchihashi S, et al. Viral interleukin-10 gene transfer prevents liver ischemia-reperfusion injury: Toll-like receptor-4 and heme oxygenase-1 signaling in innate and adaptive immunity [Ｊ]. 〖ＪＰ4〗Hum Gene Ther, 2007; 18(4): 355-366.
22.	Zwacka RM, Zhou W, Zhang Y, et al. Redox gene therapy for ischemia/reperfusion injury of the liver reduces AP1 and NF-kappaB activation [Ｊ]. Nat Med, 1998; 4(6): 698-704.
23.	Wheeler MD, Katuna M, Smutney OM, et al. Comparison of the effect of adenoviral delivery of three superoxide dismutase genes against hepatic ischemia-reperfusion injury [Ｊ]. Hum Gene Ther, 2001; 12(18): 2167-2177.
24.	Katori M, Buelow R, Ke B, et al. Heme oxygenase-1 overexpression protects rat hearts from cold ischemia/reperfusion injury via an antiapoptotic pathway [Ｊ]. Transplantation, 2002; 73(2): 287-292.
25.	Soares MP, Lin Y, Anrather J, et al. Expression of heme oxygenase-1 can determine cardiac xenograft survival [Ｊ]. Nat Med, 1998; 4(9): 1073-1077.
26.	Otterbein LE, Kolls JK, Mantell LL, et al. Exogenous administration of heme oxygenase-1 by gene transfer provides protection against hyperoxia-induced lung injury [Ｊ]. J Clin Invest, 1999; 103(7): 1047-1054.
27.	Kuboki S, Schuster R, Blanchard J, et al. Role of heat shock protein 70 in hepatic ischemia-reperfusion injury in mice [Ｊ]. Am J Physiol Gastrointest Liver Physiol, 2007; 292(4): G1141-G1149.
28.	王科，王学浩，张峰，等. 诱导HO-1改善氧化应激状态减轻老年供肝缺血再灌注损伤 [Ｊ]. 中国普外基础与临床杂志, 2005; 12(2): 109-112.
29.	Shen SQ, Zhang Y, Xiang JJ, et al. Protective effect of curcumin against liver warm ischemia/reperfusion injury in rat model is associated with regulation of heat shock protein and antioxidant enzymes [Ｊ]. World J Gastroenterol, 2007; 13(13): 1953-1961.
30.	Zuo Z, Wang C, Carpenter D, et al. Prolongation of allograft survival with viral IL-10 transfection in a highly histoincompatible model of rat heart allograft rejection [Ｊ]. Transplantation, 2001; 71(5): 686-691.
31.	Ke B, 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.
32.	Evans PC, Kilshaw PJ. Interleukin-13 protects endothelial cells from apoptosis and activation: association with the protective genes A20 and A1 [Ｊ]. Transplantation, 2000; 70(6): 928-934.
33.	Kim YI, Song KE, Ryeon HK, et al. Enhanced inflammatory cytokine production at ischemia/reperfusion in human liver resection [Ｊ]. Hepatogastroenterology, 2002; 49(46): 1077-1082.
34.	Ahmed-Choudhury J, Russell CL, Randhawa S, et al. Differential induction of nuclear factor-kappaB and activator protein-1 activity after CD40 ligation is associated with primary human hepatocyte apoptosis or intrahepatic endothelial cell proliferation [Ｊ]. Mol Biol Cell, 2003; 14(4): 1334-1345.
35.	Nikolaidou-Neokosmidou V, Zannis VI, Kardassis D. Inhibition of hepatocyte nuclear factor 4 transcriptional activity by the nuclear factor kappaB pathway [Ｊ]. Biochem J, 2006; 398(3): 439-450.
36.	Takahashi Y, Ganster RW, Ishikawa T, et al. Protective role of NF-kappaB in liver cold ischemia/reperfusion injury: effects of IkappaB gene therapy [Ｊ]. Transplant Proc, 2001; 33(1-2): 602.
37.	Shen XD, Ke B, Zhai Y, 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 [Ｊ]. Transplantation, 2002; 74(3): 315-319.
38.	Shen XD, Ke B, Zhai Y, et al. Stat4 and Stat6 signaling in hepatic ischemia/reperfusion injury in mice: HO-1 dependence of Stat4 disruption-mediated cytoprotection [Ｊ]. Hepatology, 2003; 37(2): 296-319.
39.	Ke B, Shen XD, Gao F, et al. 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 [Ｊ]. Mol Ther, 2004; 9(1): 38-45.
40.	Sato Y, Ajiki T, Inoue S, et al. Gene silencing in rat-liver and limb grafts by rapid injection of small interference RNA [Ｊ]. Transplantation, 2005; 79(2): 240-243.
41.	Soutschek J, Akinc A, Bramlage B, et al. Therapeutic silencing of an endogenous gene by systemic administration of modified siRNAs [Ｊ]. Nature, 2004; 432(7014): 173-178.

1. Jennings ER, Hindmarsh C. Hemagglutination test for viral hepatitis with special reference to nonspecific reactions[Ｊ]. J Lab Clin Med, 1960; 55: 519-521.
2. Suzuki F, Hashikura Y, Ise H, et al. MCI-186 (edaravone), a free radical scavenger, attenuates hepatic warm ischemia-reperfusion injury in rats [Ｊ]. Transpl Int, 2005; 18(7): 844-853.
3. Nakatani K, Kaneda K, Seki S, et al. Pit cells as liver-associated natural killer cells: morphology and function [Ｊ]. Med Electron Microsc, 2004; 37(1): 29-36.
4. Teoh N, Field J, Sutton J, et al. Dual role of tumor necrosis factor-alpha in hepatic ischemia-reperfusion injury: studies in tumor necrosis factor-alpha gene knockout mice [Ｊ]. Hepatology, 2004; 39(2): 412-421.
5. Zhai Y, Shen XD, Hancock WW, et al. CXCR3+CD4+ T cells mediate innate immune function in the pathophysiology of liver ischemia/reperfusion injury [Ｊ]. J Immunol, 2006; 176(10): 6313-6322.〖ＪP〗.
6. Fischer M, Harvima IT, Carvalho RF, et al. Mast cell CD30 ligand is upregulated in cutaneous inflammation and mediates degranulation-independent chemokine secretion [Ｊ]. J Clin Invest, 2006; 116(10): 2748-2756.
7. Odashima M, Otaka M, Jin M, et al. Selective A2A adenosine agonist ATL-146e attenuates acute lethal liver injury in mice [Ｊ]. J Gastroenterol, 2005; 40(5): 526-529.
8. Mizuguchi H, Hayakawa T. Targeted adenovirus vectors [Ｊ]. Hum Gene Ther, 2004; 15(11): 1034-1044.
9. Savransky V, Molls RR, Burne-Taney M, et al. Role of the T-cell receptor in kidney ischemia-reperfusion injury [Ｊ]. Kidney Int, 2006; 69(2): 233-238.
10. Ke B, Shen XD, Gao F, et al. Interleukin 13 gene transfer in liver ischemia and reperfusion injury: role of Stat6 and TLR4 pathways in cytoprotection [Ｊ]. Hum Gene Ther, 2004; 15(7): 691-698.
11. Berberat PO, Katori M, Kaczmarek E, et al. Heavy chain ferritin acts as an antiapoptotic gene that protects livers from ischemia reperfusion injury [Ｊ]. FASEB J, 2003; 17(12): 1724-1726.
12. Caldwell CC, Okaya T, Martignoni A, et al. Divergent functions of CD4+ T lymphocytes in acute liver inflammation and injury after ischemia-reperfusion [Ｊ]. Am J Physiol Gastrointest Liver Physiol, 2005; 289(5): G969-G976.
13. Day YJ, Marshall MA, Huang L, et al. Protection from ischemic liver injury by activation of A2A adenosine receptors during reperfusion: inhibition of chemokine induction [Ｊ]. Am J Physiol Gastrointest Liver Physiol, 2004; 286(2): G285-G293.
14. Zhang M, Alicot EM, Chiu I, et al. Identification of the target self-antigens in reperfusion injury [Ｊ]. J Exp Med, 2006; 203(1): 141-152.
15. Gao W, Bentley RC, Madden JF, et al. Apoptosis of sinusoidal endothelial cells is a critical mechanism of preservation injury in rat liver transplantation [Ｊ]. Hepatology, 1998; 27(6): 1652-1660.
16. Bilbao G, Contreras JL, Eckhoff DE, et al. Reduction of ischemia-reperfusion injury of the liver by in vivo adenovirus-mediated gene transfer of the antiapoptotic Bcl-2 gene [Ｊ]. Ann Surg, 1999; 230(2): 185-193.
17. Barrier A, Olaya N, Chiappini F, et al. Ischemic preconditioning modulates the expression of several genes, leading to the overproduction of IL-1Ra, iNOS, and Bcl-2 in a human model of liver ischemia-reperfusion [Ｊ]. FASEB J, 2005; 19(12): 1617-1626.
18. Ma W, Wang ZR, Shi L, et al. Expression of macrophage inflammatory protein-1 alpha in Kupffer cells following liver ischemia or reperfusion injury in rats [Ｊ]. World J Gastroenterol, 2006; 12(24): 3854-3858.
19. Sawitzki B, Amersi F, Ritter T, et al. Upregulation of Bag-1 by ex vivo gene transfer protects rat livers from ischemia/reperfusion injury [Ｊ]. Hum Gene Ther, 2002; 13(12): 1495-1504.
20. El-Ghoneimi A, Cursio R, Schmid-Alliana A, et al. Inhibition of tumor necrosis factor alpha gene transcription by pentoxifylline reduces normothermic liver ischemia-reperfusion injury in rats [Ｊ]. Transplant Proc, 2007; 39(6): 1761-1764.
21. Ke B, Shen XD, Tsuchihashi S, et al. Viral interleukin-10 gene transfer prevents liver ischemia-reperfusion injury: Toll-like receptor-4 and heme oxygenase-1 signaling in innate and adaptive immunity [Ｊ]. 〖ＪＰ4〗Hum Gene Ther, 2007; 18(4): 355-366.
22. Zwacka RM, Zhou W, Zhang Y, et al. Redox gene therapy for ischemia/reperfusion injury of the liver reduces AP1 and NF-kappaB activation [Ｊ]. Nat Med, 1998; 4(6): 698-704.
23. Wheeler MD, Katuna M, Smutney OM, et al. Comparison of the effect of adenoviral delivery of three superoxide dismutase genes against hepatic ischemia-reperfusion injury [Ｊ]. Hum Gene Ther, 2001; 12(18): 2167-2177.
24. Katori M, Buelow R, Ke B, et al. Heme oxygenase-1 overexpression protects rat hearts from cold ischemia/reperfusion injury via an antiapoptotic pathway [Ｊ]. Transplantation, 2002; 73(2): 287-292.
25. Soares MP, Lin Y, Anrather J, et al. Expression of heme oxygenase-1 can determine cardiac xenograft survival [Ｊ]. Nat Med, 1998; 4(9): 1073-1077.
26. Otterbein LE, Kolls JK, Mantell LL, et al. Exogenous administration of heme oxygenase-1 by gene transfer provides protection against hyperoxia-induced lung injury [Ｊ]. J Clin Invest, 1999; 103(7): 1047-1054.
27. Kuboki S, Schuster R, Blanchard J, et al. Role of heat shock protein 70 in hepatic ischemia-reperfusion injury in mice [Ｊ]. Am J Physiol Gastrointest Liver Physiol, 2007; 292(4): G1141-G1149.
28. 王科，王学浩，张峰，等. 诱导HO-1改善氧化应激状态减轻老年供肝缺血再灌注损伤 [Ｊ]. 中国普外基础与临床杂志, 2005; 12(2): 109-112.
29. Shen SQ, Zhang Y, Xiang JJ, et al. Protective effect of curcumin against liver warm ischemia/reperfusion injury in rat model is associated with regulation of heat shock protein and antioxidant enzymes [Ｊ]. World J Gastroenterol, 2007; 13(13): 1953-1961.
30. Zuo Z, Wang C, Carpenter D, et al. Prolongation of allograft survival with viral IL-10 transfection in a highly histoincompatible model of rat heart allograft rejection [Ｊ]. Transplantation, 2001; 71(5): 686-691.
31. Ke B, 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.
32. Evans PC, Kilshaw PJ. Interleukin-13 protects endothelial cells from apoptosis and activation: association with the protective genes A20 and A1 [Ｊ]. Transplantation, 2000; 70(6): 928-934.
33. Kim YI, Song KE, Ryeon HK, et al. Enhanced inflammatory cytokine production at ischemia/reperfusion in human liver resection [Ｊ]. Hepatogastroenterology, 2002; 49(46): 1077-1082.
34. Ahmed-Choudhury J, Russell CL, Randhawa S, et al. Differential induction of nuclear factor-kappaB and activator protein-1 activity after CD40 ligation is associated with primary human hepatocyte apoptosis or intrahepatic endothelial cell proliferation [Ｊ]. Mol Biol Cell, 2003; 14(4): 1334-1345.
35. Nikolaidou-Neokosmidou V, Zannis VI, Kardassis D. Inhibition of hepatocyte nuclear factor 4 transcriptional activity by the nuclear factor kappaB pathway [Ｊ]. Biochem J, 2006; 398(3): 439-450.
36. Takahashi Y, Ganster RW, Ishikawa T, et al. Protective role of NF-kappaB in liver cold ischemia/reperfusion injury: effects of IkappaB gene therapy [Ｊ]. Transplant Proc, 2001; 33(1-2): 602.
37. Shen XD, Ke B, Zhai Y, 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 [Ｊ]. Transplantation, 2002; 74(3): 315-319.
38. Shen XD, Ke B, Zhai Y, et al. Stat4 and Stat6 signaling in hepatic ischemia/reperfusion injury in mice: HO-1 dependence of Stat4 disruption-mediated cytoprotection [Ｊ]. Hepatology, 2003; 37(2): 296-319.
39. Ke B, Shen XD, Gao F, et al. 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 [Ｊ]. Mol Ther, 2004; 9(1): 38-45.
40. Sato Y, Ajiki T, Inoue S, et al. Gene silencing in rat-liver and limb grafts by rapid injection of small interference RNA [Ｊ]. Transplantation, 2005; 79(2): 240-243.
41. Soutschek J, Akinc A, Bramlage B, et al. Therapeutic silencing of an endogenous gene by systemic administration of modified siRNAs [Ｊ]. Nature, 2004; 432(7014): 173-178.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Research Advancement on Gene Therapy for Hepatic Ischemia-Reperfusion Injury

Abstract Full text Figures/Tables Video References Cited by

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