攜帶IL-13基因肝干細胞對冷缺血大鼠移植肝臟保護作用的研究_《中國普外基礎與臨床雜志》

作者：

陳剛 ¹ , 李學成 ¹ , 吳國慶 ¹ , 楊日高 ¹ , 晉云 ² , 韓江 ² , 董家鴻 ³

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

關鍵詞：

慢病毒白介素-13 肝干細胞肝移植缺血性膽管損傷血氧合酶-1

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目的以基因工程干細胞治療的方式來改善缺血-再灌注狀況，使移植肝臟更好地耐受缺血-再灌注，以減少移植術后的并發癥，延長移植器官存活期。
方法利用已建立的Wistar大鼠冷缺血原位肝移植(OLT)模型，術中經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胞（HOC）即轉染組和未轉染組，分別于術后1、3、7及14 d檢測受體大鼠肝臟功能變化、組織學變化、膽管上皮細胞(BEC)的增殖情況、α-平滑肌肌動蛋白(α-SMA)的表達、肝組織中HO-1 mRNA的表達，并觀察移植大鼠術后的存活情況。
結果轉入IL-13基因的HOC對冷保存損傷的肝臟有一定的保護作用；術后7 d，肝移植組和未轉染組的α-SMA表達較轉染組明顯（P lt;0.05）；術后3 d，未轉染組和轉染組的BEC增殖指數明顯低于肝移植組（P lt;0.05）。轉染組術后各時相點的HO-1 mRNA表達水平均明顯高于相應時相點的其他各組的水平(P lt;0.05)；移植術中經門靜脈輸入HOC對缺血性膽管損傷所誘導的BEC增殖有一定的抑制作用，對BEC具有一定的保護作用；肝移植組生存率明顯低于假手術組和轉染組(P lt;0.05)。
結論 IL-13的持續表達能促進術后移植肝內HO-1 mRNA的表達，這有利于對供肝的保護，有利于受體大鼠術后肝功能的恢復。促進HO-1 mRNA的表達是IL-13對BEC的具有保護作用的機理之一。

引用本文： 陳剛,李學成,吳國慶,楊日高,晉云,韓江,董家鴻. 攜帶IL-13基因肝干細胞對冷缺血大鼠移植肝臟保護作用的研究. 中國普外基礎與臨床雜志, 2010, 17(2): 135-141. doi: 復制

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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.
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9.	黃志強, 黃曉強, 周寧新. 肝移植時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. 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, 陳規劃, 等. 重建肝動脈血供大鼠原位肝移植模型的術式探討 [J]. 中華實驗外科雜志, 2004; 21(1): 110111.
7. 陳志宇, 張玉君, 王槐志, 等. 改良法重建肝動脈血供的大鼠原位肝移植模型 [J]. 中華實驗外科雜志, 2005; 22(8): 10161017.
8. 陳剛, 韓江, 劉永康，等. 攜帶IL13基因大鼠肝干細胞系的建立 [J]. 中國普外基礎與臨床雜志, 2009; 16(4): 276280.
9. 黃志強, 黃曉強, 周寧新. 肝移植時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.

《中國普外基礎與臨床雜志》

攜帶IL-13基因肝干細胞對冷缺血大鼠移植肝臟保護作用的研究

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《中國普外基礎與臨床雜志》

攜帶IL-13基因肝干細胞對冷缺血大鼠移植肝臟保護作用的研究

摘要 全文 圖表 視頻 參考文獻 施引文獻 補充材料

Format

Content

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