• 1.解放軍第324醫(yī)院普通外科（重慶　400020）;;
  • 2.成都軍區(qū)昆明總醫(yī)院肝膽外科（昆明　650032）;;
  • 3.解放軍總醫(yī)院肝膽外科（北京 100853);

目的  以基因工程干細(xì)胞治療的方式來(lái)改善缺血-再灌注狀況，使移植肝臟更好地耐受缺血-再灌注，以減少移植術(shù)后的并發(fā)癥，延長(zhǎng)移植器官存活期。
方法  利用已建立的Wistar大鼠冷缺血原位肝移植(OLT)模型，術(shù)中經(jīng)受體大鼠門靜脈輸入IL-13基因修飾的或未修飾的肝卵圓細(xì)胞（HOC）即轉(zhuǎn)染組和未轉(zhuǎn)染組，分別于術(shù)后1、3、7及14 d檢測(cè)受體大鼠肝臟功能變化、組織學(xué)變化、膽管上皮細(xì)胞(BEC)的增殖情況、α-平滑肌肌動(dòng)蛋白(α-SMA)的表達(dá)、肝組織中HO-1 mRNA的表達(dá)，并觀察移植大鼠術(shù)后的存活情況。
結(jié)果  轉(zhuǎn)入IL-13基因的HOC對(duì)冷保存損傷的肝臟有一定的保護(hù)作用； 術(shù)后7 d，肝移植組和未轉(zhuǎn)染組的α-SMA表達(dá)較轉(zhuǎn)染組明顯（P lt;0.05）； 術(shù)后3 d，未轉(zhuǎn)染組和轉(zhuǎn)染組的BEC增殖指數(shù)明顯低于肝移植組（P lt;0.05）。轉(zhuǎn)染組術(shù)后各時(shí)相點(diǎn)的HO-1 mRNA表達(dá)水平均明顯高于相應(yīng)時(shí)相點(diǎn)的其他各組的水平(P lt;0.05)； 移植術(shù)中經(jīng)門靜脈輸入HOC對(duì)缺血性膽管損傷所誘導(dǎo)的BEC增殖有一定的抑制作用，對(duì)BEC具有一定的保護(hù)作用； 肝移植組生存率明顯低于假手術(shù)組和轉(zhuǎn)染組(P lt;0.05)。
結(jié)論  IL-13的持續(xù)表達(dá)能促進(jìn)術(shù)后移植肝內(nèi)HO-1 mRNA的表達(dá)，這有利于對(duì)供肝的保護(hù)，有利于受體大鼠術(shù)后肝功能的恢復(fù)。促進(jìn)HO-1 mRNA的表達(dá)是IL-13對(duì)BEC的具有保護(hù)作用的機(jī)理之一。

引用本文： 陳剛,李學(xué)成,吳國(guó)慶,楊日高,晉云,韓江,董家鴻. 攜帶IL-13基因肝干細(xì)胞對(duì)冷缺血大鼠移植肝臟保護(hù)作用的研究. 中國(guó)普外基礎(chǔ)與臨床雜志, 2010, 17(2): 135-141. doi: 復(fù)制

版權(quán)信息： ?四川大學(xué)華西醫(yī)院華西期刊社《中國(guó)普外基礎(chǔ)與臨床雜志》版權(quán)所有，未經(jīng)授權(quán)不得轉(zhuǎn)載、改編

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. 馬毅, 何曉順, 陳規(guī)劃, 等. 重建肝動(dòng)脈血供大鼠原位肝移植模型的術(shù)式探討 [J]. 中華實(shí)驗(yàn)外科雜志, 2004; 21(1): 110111.
7. 陳志宇, 張玉君, 王槐志, 等. 改良法重建肝動(dòng)脈血供的大鼠原位肝移植模型 [J]. 中華實(shí)驗(yàn)外科雜志, 2005; 22(8): 10161017.
8. 陳剛, 韓江, 劉永康， 等. 攜帶IL13基因大鼠肝干細(xì)胞系的建立 [J]. 中國(guó)普外基礎(chǔ)與臨床雜志, 2009; 16(4): 276280.
9. 黃志強(qiáng), 黃曉強(qiáng), 周寧新. 肝移植時(shí)代終末期膽病的治療-回顧與反思 [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. 董家鴻. 膽道并發(fā)癥： 肝移植的“阿喀琉斯之踵” [J]. 中華普通外科雜志, 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. 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. 2. Fisher A, Miller CH. Ischemictype biliary strictures in liver allografts: the Achilles heel revisited? [J]. Hepatology, 1995; 21 (2): 589591.
  3. 3. Tung BY, Kimmey MB. Biliary complications of orthotopic liver transplantation [J]. Dig Dis, 1999; 17(3): 133144.
  4. 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. 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. 6. 馬毅, 何曉順, 陳規(guī)劃, 等. 重建肝動(dòng)脈血供大鼠原位肝移植模型的術(shù)式探討 [J]. 中華實(shí)驗(yàn)外科雜志, 2004; 21(1): 110111.
  7. 7. 陳志宇, 張玉君, 王槐志, 等. 改良法重建肝動(dòng)脈血供的大鼠原位肝移植模型 [J]. 中華實(shí)驗(yàn)外科雜志, 2005; 22(8): 10161017.
  8. 8. 陳剛, 韓江, 劉永康， 等. 攜帶IL13基因大鼠肝干細(xì)胞系的建立 [J]. 中國(guó)普外基礎(chǔ)與臨床雜志, 2009; 16(4): 276280.
  9. 9. 黃志強(qiáng), 黃曉強(qiáng), 周寧新. 肝移植時(shí)代終末期膽病的治療-回顧與反思 [J]. 消化外科, 2002; 1(6): 381392.
  10. 10. Strazzabosco M, Spirli C, Ololicsanyi L. Pathophysiology of the intrahepatic biliary epithelium [J]. J Gastroenterol Hepatol, 2000; 15(3): 244253.
  11. 11. 董家鴻. 膽道并發(fā)癥： 肝移植的“阿喀琉斯之踵” [J]. 中華普通外科雜志, 2005; 20（8）: 465466.
  12. 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. 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. 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. 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. 16. Krawczyk M, Nyckowski P, Zieniewicz K, et al. Biliary complications following liver transplantation [J]. Transplant Proc, 2000; 32(6): 14291431.
  17. 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. 18. Larrey D, Pageaux GP. Genetic predisposition to druginduced hepatotoxicity [J]. J Hepatol, 1997; 26(Suppl 12): 1221.
  19. 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. 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. 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. 22. Alison MR, Poulsom R, Jeffery R, et al. Hepatocytes from nonhepatic adult stem cells [J]. Nature, 2000; 406(6793): 257.
  23. 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. 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. 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. 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. 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. 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. 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.