Study on Protective Effects of IL-13 Gene-Modified Rattus Hepatic Stem Cells on Cold Ischemia Transplant Liver_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

CHEN Gang ¹ , LI Xuecheng ¹ , WU Guoqing ¹ , YANG Rigao ¹ , JIN Yun ² , HAN Jiang ² , DONG Jiahong ³

1.Department of General Surgery, The No.324 Hospital of PLA, Chongqing 400020, China;;
2.Department of Hepatobiliary Surgery, Kunming General Hospital, Chengdu Military Region, Kunming 650032, China;;
3.Department of Hepatobiliary Surgery, General Hospital of PLA, Beijing 100853, China;

Corresponding author：

Keywords：

Lentivirus; Interleukin-13; Hepatic stem cell; Liver transplantation; Ischemia-type biliary lesion; Heme oxygenase1

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Objective Biliary epithelial cell (BEC) proliferated actively induced by ischemia-type biliary lesion (ITBL), which played an important role in the development of biliary complication after orthortopic liver transplantation (OLT). The aims of this study is to provide novel method to protect the liver endured cold preservation and reperfusion injury (CPRI) and reduce posttransplant biliary complication, and explore its possible mechanism.
Methods Based on constructed OLT models for studying ITBL, the hepatic oval cell (HOC) or the IL-13 genemodified HOC to the portal vein of the recipient 〔OLT+HOC group and OLT+IL-13· HOC group〕 were-transfused, then the pathology change, the liver function and the expressions of the α-smooth muscle actin (αSMA) and Heme oxygenase-1 (HO-1) mRNA of the transplanted liver of CPRI were observed, the proliferation of BEC and survival rate of the recipients were also observed.
Results The BEC injury was showed in grafts with prolonged ischemia time, characterized by induction of BEC proliferation, liver function injury and cholestasis sign reflecting the increase of serum ALT, AST and TBIL. The OLT+IL-13·HOC group had better results than OLT and OLT+HOC group, which indicated the OLT+IL-13·HOC group had low level of expression α-SMA (after operation 7 d, P lt;0.05) and proliferation of BEC (after operation 3 d, P lt;0.05). The expressions of HO-1 mRNA were higher in OLT+IL-13·HOC group than in other groups. The survival rate of OLT group was lower than that of the OLT+IL-13·HOC group and sham operation group (P lt;0.05).
Conclusion High expression level of IL-13 in recipient rats could promote the expression of HO-1 mRNA in transplant liver, and profit to protection donor liver, and recover of the liver function after liver transplantation. It perhaps is the mechanism of protective effect of IL-13 on graft that stimulate the expression of HO-1 mRNA significantly.

Citation： CHEN Gang ,LI Xuecheng,WU Guoqing,YANG Rigao,JIN Yun,HAN Jiang,DONG Jiahong. Study on Protective Effects of IL-13 Gene-Modified Rattus Hepatic Stem Cells on Cold Ischemia Transplant Liver. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2010, 17(2): 135-141. doi: Copy

1.	Calne RY. A new technique for biliary drainage in orthotopic liver transplantation utilizing the gallbladder as a pedicle conduit between the donor and recipient common bile ducts [J]. Ann Surg, 1976; 184(5): 605609.
2.	Fisher A, Miller CH. Ischemictype biliary strictures in liver allografts: the Achilles heel revisited? [J]. Hepatology, 1995; 21 (2): 589591.
3.	Tung BY, Kimmey MB. Biliary complications of orthotopic liver transplantation [J]. Dig Dis, 1999; 17(3): 133144.
4.	Kamada N, Calne RY. Orthotopic liver transplantation in the rat: Technique using cuff for portal vein anastomosis and biliary drainage [J]. Transplantation, 1979; 28(1): 4750.
5.	Gao W, Lemasters JJ, Thurman RG. Development of a new method for hepatic rearterialization in rat orthotopic liver transplantation: Reduction of liver injury and improvement of surgical outcome by arterialization [J]. Transplantation, 1993; 56(1): 1924.
6.	马毅, 何晓顺, 陈规划, 等. 重建肝动脉血供大鼠原位肝移植模型的术式探讨 [J]. 中华实验外科杂志, 2004; 21(1): 110111.
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8.	陈刚, 韩江, 刘永康，等. 携带IL13基因大鼠肝干细胞系的建立 [J]. 中国普外基础与临床杂志, 2009; 16(4): 276280.
9.	黄志强, 黄晓强, 周宁新. 肝移植时代终末期胆病的治疗-回顾与反思 [J]. 消化外科, 2002; 1(6): 381392.
10.	Strazzabosco M, Spirli C, Ololicsanyi L. Pathophysiology of the intrahepatic biliary epithelium [J]. J Gastroenterol Hepatol, 2000; 15(3): 244253.
11.	董家鸿. 胆道并发症：肝移植的“阿喀琉斯之踵” [J]. 中华普通外科杂志, 2005; 20（8）: 465466.
12.	SanchezUrdazpal L, Gores GJ, Ward EM, et al. Diagnostic features and clinical outcome of ischemic type biliary complications after orthotopic liver transplantation [J]. Hepatology, 1993; 17(4): 605609.
13.	Schlitt HJ, Meier PN, Nashan B, et al. Reconstructive surgery for ischemic type lesions at the bile duct bifurcation after liver transplantation.hepatology [J]. Ann Surg, 1999; 229(1): 137145.
14.	Moench C, Moench K, Lohse AW, et al. Prevention of ischemic type biliary lesions by arterial back table pressure perfusion [J]. Liver Transpl, 2003; 9(3): 285289.
15.	Boraschi P, Donati F, Gigoni R, et al. Ischemictype biliary lesions in liver transplant recipients: evaluation with magnetic resonance cholangiography [J]. Transplant Proc, 2004; 36(9): 27442747.
16.	Krawczyk M, Nyckowski P, Zieniewicz K, et al. Biliary complications following liver transplantation [J]. Transplant Proc, 2000; 32(6): 14291431.
17.	Matsumura S, Van de Water J, Leung P, et al. Caspase induction by IgA antimitochondrial antibody: IgAmediated biliary injury in primary biliary cirrhosis [J]. Hepatology, 2004; 39(5): 14151422.
18.	Larrey D, Pageaux GP. Genetic predisposition to druginduced hepatotoxicity [J]. J Hepatol, 1997; 26(Suppl 12): 1221.
19.	Ros JE, Libbrecht L, Geuken M, et al. High expression of MDR1, MRP1, and MRP3 in the hepatic progenitor compartment and hepatocytes in severe human liver disease [J]. J Pathol, 2003; 200(5): 553560.
20.	Jacquemin E, De Vree JM, Cresteil D, et al. The wide spectrum of MDR3 deficiency: from neonatal cholestasis to cirrhosis of adulthood [J]. Gastroenterology, 2001; 120(6): 14481458.
21.	Theise ND, Badve S, Saxena R, et al. Derivation of hepatocytes form bone marrow cells in mice after radiation induced myeloablation [J]. Hepatology, 2000; 31(1): 235240.
22.	Alison MR, Poulsom R, Jeffery R, et al. Hepatocytes from nonhepatic adult stem cells [J]. Nature, 2000; 406(6793): 257.
23.	Chomarat P, Banchereau J. Interleukin4 and interleukin13: their similarities and discrepancies [J]. Int Rev Immunol, 1998; 17(14): 152.
24.	Gorczynski RM, Cohen Z, Fu XM, et al. Interleukin13, in combination with antiinterleukin12, increasees graft prolongation after portal venous immunization with cultured allogeneic bone marrowderived dendritic cells [J]. Transplantation, 1996; 62(11): 15921600.
25.	Nakamura N, Nishida S, Neff GR, et al. Intrahepatic biliary strictures without hepatic artery thrombosis after liver transplantation: an analysis of 1 113 liver transplantations at a Single center [J]. Transplantation, 2005; 79(4): 427432.
26.	Choi AM, Alam J. Heme oxygenase1: function, regulation, and implication of a novel stressinducible protein in oxidantinduced lung injury [J]. Am J Respir Cell Mol Biol, 1996; 15(1): 919.
27.	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.
28.	Tullius SG, NieminenKelha M, Buelow R, et al. Inhibition of ischemia/reperfusion injury and chronic graft deterioration by a singledonor treatment with cobaltprotoporphyrin for the induction of heme oxygenase1 [J]. Transplantation, 2002; 74(5): 591598.
29.	Camara NO, Soares MP. Heme oxygenase1 (HOl), a protecrive gene that prevents chronic graft dysfunction [J]. Free Radic Biol Med, 2005; 38(4): 426435.

1. Calne RY. A new technique for biliary drainage in orthotopic liver transplantation utilizing the gallbladder as a pedicle conduit between the donor and recipient common bile ducts [J]. Ann Surg, 1976; 184(5): 605609.
2. Fisher A, Miller CH. Ischemictype biliary strictures in liver allografts: the Achilles heel revisited? [J]. Hepatology, 1995; 21 (2): 589591.
3. Tung BY, Kimmey MB. Biliary complications of orthotopic liver transplantation [J]. Dig Dis, 1999; 17(3): 133144.
4. Kamada N, Calne RY. Orthotopic liver transplantation in the rat: Technique using cuff for portal vein anastomosis and biliary drainage [J]. Transplantation, 1979; 28(1): 4750.
5. Gao W, Lemasters JJ, Thurman RG. Development of a new method for hepatic rearterialization in rat orthotopic liver transplantation: Reduction of liver injury and improvement of surgical outcome by arterialization [J]. Transplantation, 1993; 56(1): 1924.
6. 马毅, 何晓顺, 陈规划, 等. 重建肝动脉血供大鼠原位肝移植模型的术式探讨 [J]. 中华实验外科杂志, 2004; 21(1): 110111.
7. 陈志宇, 张玉君, 王槐志, 等. 改良法重建肝动脉血供的大鼠原位肝移植模型 [J]. 中华实验外科杂志, 2005; 22(8): 10161017.
8. 陈刚, 韩江, 刘永康，等. 携带IL13基因大鼠肝干细胞系的建立 [J]. 中国普外基础与临床杂志, 2009; 16(4): 276280.
9. 黄志强, 黄晓强, 周宁新. 肝移植时代终末期胆病的治疗-回顾与反思 [J]. 消化外科, 2002; 1(6): 381392.
10. Strazzabosco M, Spirli C, Ololicsanyi L. Pathophysiology of the intrahepatic biliary epithelium [J]. J Gastroenterol Hepatol, 2000; 15(3): 244253.
11. 董家鸿. 胆道并发症：肝移植的“阿喀琉斯之踵” [J]. 中华普通外科杂志, 2005; 20（8）: 465466.
12. SanchezUrdazpal L, Gores GJ, Ward EM, et al. Diagnostic features and clinical outcome of ischemic type biliary complications after orthotopic liver transplantation [J]. Hepatology, 1993; 17(4): 605609.
13. Schlitt HJ, Meier PN, Nashan B, et al. Reconstructive surgery for ischemic type lesions at the bile duct bifurcation after liver transplantation.hepatology [J]. Ann Surg, 1999; 229(1): 137145.
14. Moench C, Moench K, Lohse AW, et al. Prevention of ischemic type biliary lesions by arterial back table pressure perfusion [J]. Liver Transpl, 2003; 9(3): 285289.
15. Boraschi P, Donati F, Gigoni R, et al. Ischemictype biliary lesions in liver transplant recipients: evaluation with magnetic resonance cholangiography [J]. Transplant Proc, 2004; 36(9): 27442747.
16. Krawczyk M, Nyckowski P, Zieniewicz K, et al. Biliary complications following liver transplantation [J]. Transplant Proc, 2000; 32(6): 14291431.
17. Matsumura S, Van de Water J, Leung P, et al. Caspase induction by IgA antimitochondrial antibody: IgAmediated biliary injury in primary biliary cirrhosis [J]. Hepatology, 2004; 39(5): 14151422.
18. Larrey D, Pageaux GP. Genetic predisposition to druginduced hepatotoxicity [J]. J Hepatol, 1997; 26(Suppl 12): 1221.
19. Ros JE, Libbrecht L, Geuken M, et al. High expression of MDR1, MRP1, and MRP3 in the hepatic progenitor compartment and hepatocytes in severe human liver disease [J]. J Pathol, 2003; 200(5): 553560.
20. Jacquemin E, De Vree JM, Cresteil D, et al. The wide spectrum of MDR3 deficiency: from neonatal cholestasis to cirrhosis of adulthood [J]. Gastroenterology, 2001; 120(6): 14481458.
21. Theise ND, Badve S, Saxena R, et al. Derivation of hepatocytes form bone marrow cells in mice after radiation induced myeloablation [J]. Hepatology, 2000; 31(1): 235240.
22. Alison MR, Poulsom R, Jeffery R, et al. Hepatocytes from nonhepatic adult stem cells [J]. Nature, 2000; 406(6793): 257.
23. Chomarat P, Banchereau J. Interleukin4 and interleukin13: their similarities and discrepancies [J]. Int Rev Immunol, 1998; 17(14): 152.
24. Gorczynski RM, Cohen Z, Fu XM, et al. Interleukin13, in combination with antiinterleukin12, increasees graft prolongation after portal venous immunization with cultured allogeneic bone marrowderived dendritic cells [J]. Transplantation, 1996; 62(11): 15921600.
25. Nakamura N, Nishida S, Neff GR, et al. Intrahepatic biliary strictures without hepatic artery thrombosis after liver transplantation: an analysis of 1 113 liver transplantations at a Single center [J]. Transplantation, 2005; 79(4): 427432.
26. Choi AM, Alam J. Heme oxygenase1: function, regulation, and implication of a novel stressinducible protein in oxidantinduced lung injury [J]. Am J Respir Cell Mol Biol, 1996; 15(1): 919.
27. 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.
28. Tullius SG, NieminenKelha M, Buelow R, et al. Inhibition of ischemia/reperfusion injury and chronic graft deterioration by a singledonor treatment with cobaltprotoporphyrin for the induction of heme oxygenase1 [J]. Transplantation, 2002; 74(5): 591598.
29. Camara NO, Soares MP. Heme oxygenase1 (HOl), a protecrive gene that prevents chronic graft dysfunction [J]. Free Radic Biol Med, 2005; 38(4): 426435.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Study on Protective Effects of IL-13 Gene-Modified Rattus Hepatic Stem Cells on Cold Ischemia Transplant Liver

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