Mechanism of Effect of Hepatic Artery Ischemia on Biliary Fibrosis after Liver Transplantation and Prevention Method_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

LU Hongwei ^1,2 , LI Yiming ² , JI Hong ² , DONG Jiahong ¹

1.Department of Hepato-Biliary Surgery, Chinese PLA General Hospital, Beijing 100853, China;;
2.Department of General Surgery, The Second Affiliated Hospital, Medical College, Xi’an Jiaotong University, Xi’an 710004, China;

Corresponding author：

Keywords：

Liver transplantation; Biliary fibrosis; Hepatic artery ischemia; Transforming growth factor-β1; α-smooth muscle actin

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Objective To validate the mechanism of effect of hepatic artery ischemia on biliary fibrosis after liver transplantation and the prevention method.
Methods Eighteen male dogs were established into the concise auto orthotopic liver transplantation models and assigned into three groups randomly: hepatic artery ischemia (HAI) group, TBB group (transferred the blood by a bridge duct ) and control group, each group contained 6 dogs. After opening portal vein, the samples were cut from liver in each group at the time of 6 h, 3 d and 14 d. The pathological modifications of intrahepatic bile ducts were observed and expression of transforming growth factor-β1 (TGF-β1) were detected in the three times. Expressions of Smad3 and phosphate-Smad3 as well as mRNA of α-smooth muscle actin (α-SMA) in intrahepatic bile ducts were detected 14 d after opening portal vein.
Results Compared with control group, the collagen deposition and lumens stenosis in biliary vessel wall were more obviously in HAI group. In TBB group, the pathological modifications were slighter compared with HAI group. The positive cell index of TGF-β1 reached peak on day 3 after opening portal vein, then decreased in TBB group, and which in HAI group kept increase and was significantly higher than that in TBB group （P lt;0.05）. The expression level of phosphate-Smad3 and transcriptional level of α-SMA mRNA were 1.04±0.13 and 1.12±0.55 in TBB group on day 14 after opening portal vein, which were significantly higher than those in control group (0.59±0.09 and 0.46±0.18) and lower than those in HAI group (1.82±0.18 and 1.86±0.73), the diversities among three groups were significant (P lt;0.05). There was not significant difference of expression of Smads among three groups (P gt;0.05).
Conclusions Hepatic artery ischemia could increase the deposition of collagen fibers and the transdifferentiation of myofibroblast in bile duct and result in the biliary fibrosis by activating the TGF-β1/Smads signaling pathway. The bridging bypass device could lessen the biliary fibrosis caused by hepatic artery ischemia by inhibiting the activation of TGF-β1/Smads signal transduction passageway.

Citation： LU Hongwei ,LI Yiming,JI Hong,DONG Jiahong. Mechanism of Effect of Hepatic Artery Ischemia on Biliary Fibrosis after Liver Transplantation and Prevention Method. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2010, 17(5): 433-438. doi: Copy

1.	Brockmann JG, August C, Wolters HH, et al. Sequence of reperfusion influences ischemia/reperfusion injury and primary graft function following porcine liver transplantation [J]. Liver Transpl, 2005; 11(10): 1214-1222.
2.	Polak WG, Porte RJ. The sequence of revascularization in liver transplantation: it does make a difference [J]. Liver Transpl, 2006; 12(11): 1566-1570, Comment on: 1607-1614.
3.	Sankary HN, McChesney L, Frye E, et al. A simple modification in operative technique can reduce the incidence of nonanastomotic biliary strictures after orthotopic liver transplantation [J]. Hepatology, 1995; 21(1): 63-69.
4.	汪雷，邓小强，舒艺，等. 神经生长因子及其受体在胆管结缔组织中的表达及意义 [J]. 中国普外基础与临床杂志， 2009； 16(1): 39-43.
5.	所广军，张辉，赵中辛. 用Western blot法区分胆道、胃部疾病癌胚抗原及其相关物质的研究 [J]. 中国普外基础与临床杂志， 2006； 13（2）： 208-210.
6.	Nakatani T, Honda E, Hayakawa S, et al. Effects of decorin on the expression of alpha-smooth muscle actin in a human myofibroblast cell line [J]. Mol Cell Biochem, 2008; 308(1-2): 201-207.
7.	As AB, Lotz Z, Tyler M, et al. Impact of early arterialization in the liver allograft [J]. Transplant Proc, 1999; 31(1-2): 406-407.
8.	Noun R, Sauvanet A, Belghiti J. Appraisal of the order of revascularization in human liver grafting: a controlled study [J]. J Am Coll Surg, 1997; 185(1): 70-73.
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12.	Northover JM, Terblanche J. A new look at the arterial supply of the bile duct in man and its surgical implications [J]. Br J Surg, 1979; 66(6): 379-384.
13.	Nishida S, Nakamura N, Kadono J, et al. Intrahepatic biliary strictures after liver transplantation [J]. J Hepatobiliary Pancreat Surg, 2006; 13(6): 511-516.
14.	Verdonk RC, Buis CI, Porte RJ, et al. Biliary complications after liver transplantation: a review [J]. Scand J Gastroenterol Suppl, 2006; (243): 89-101.
15.	Toledo-Pereyra LH, Toledo AH, Walsh J, et al. Molecular signaling pathways in ischemia/reperfusion [J]. Exp Clin Transplant, 2004; 2(1): 174-177.
16.	Wynn TA. Cellular and molecular mechanisms of fibrosis [J]. J Pathol, 2008; 214(2): 199-210.
17.	Gran JT, Molberg , Midtvedt . Pathophysiologic aspects of systemic sclerosis [J]. Tidsskr Nor Laegeforen, 2005; 125(19): 2622-2623.
18.	耿智敏，向国安，韩庆，等．转化生长因子β1在胆管愈合过程中的表达及意义 [J]．中国普外基础与临床杂志， 2000； 7（6）： 362-363．.
19.	Xu L. Regulation of Smad activities [J]. Biochim Biophys Acta, 2006; 1759(11-12): 503-513.
20.	Chen W, Fu X, Sheng Z. Review of current progress in the structure and function of Smad proteins [J]. Chin Med J (Engl), 2002; 115(3): 446-450.
21.	Hinz B, Gabbiani G. Cell-matrix and cell-cell contacts of myofibroblasts: role in connective tissue remodeling [J]. Thromb Haemost, 2003; 90(6): 993-1002.
22.	Nowak D, Popow-Woz＇niak A, Raz＇nikiewicz L, et al. Actin in the wound healing process [J]. Postepy Biochem, 2009; 55(2): 138-144.
23.	Eyden B. The myofibroblast: phenotypic characterization as a prerequisite to understanding its functions in translational medicine [J]. J Cell Mol Med, 2008; 12(1): 22-37.
24.	Liu Y. Epithelial to mesenchymal transition in renal fibrogenesis: pathologic significance, molecular mechanism, and therapeutic intervention [J]. J Am Soc Nephrol, 2004; 15(1): 1-12.
25.	Zeisberg M, Kalluri R. The role of epithelial-to-mesenchymal transition in renal fibrosis [J]. J Mol Med, 2004; 82(3): 175-181.

1. Brockmann JG, August C, Wolters HH, et al. Sequence of reperfusion influences ischemia/reperfusion injury and primary graft function following porcine liver transplantation [J]. Liver Transpl, 2005; 11(10): 1214-1222.
2. Polak WG, Porte RJ. The sequence of revascularization in liver transplantation: it does make a difference [J]. Liver Transpl, 2006; 12(11): 1566-1570, Comment on: 1607-1614.
3. Sankary HN, McChesney L, Frye E, et al. A simple modification in operative technique can reduce the incidence of nonanastomotic biliary strictures after orthotopic liver transplantation [J]. Hepatology, 1995; 21(1): 63-69.
4. 汪雷，邓小强，舒艺，等. 神经生长因子及其受体在胆管结缔组织中的表达及意义 [J]. 中国普外基础与临床杂志， 2009； 16(1): 39-43.
5. 所广军，张辉，赵中辛. 用Western blot法区分胆道、胃部疾病癌胚抗原及其相关物质的研究 [J]. 中国普外基础与临床杂志， 2006； 13（2）： 208-210.
6. Nakatani T, Honda E, Hayakawa S, et al. Effects of decorin on the expression of alpha-smooth muscle actin in a human myofibroblast cell line [J]. Mol Cell Biochem, 2008; 308(1-2): 201-207.
7. As AB, Lotz Z, Tyler M, et al. Impact of early arterialization in the liver allograft [J]. Transplant Proc, 1999; 31(1-2): 406-407.
8. Noun R, Sauvanet A, Belghiti J. Appraisal of the order of revascularization in human liver grafting: a controlled study [J]. J Am Coll Surg, 1997; 185(1): 70-73.
9. 黎一鸣, 徐金锴, 吉鸿, 等. 门静脉、肝动脉同时灌注对供肝动脉缺血损伤的保护作用 [J]. 中国普外基础与临床杂志， 2005; 12(5): 473-476, 479.
10. Sadler KM, Walsh TS, Garden OJ, et al. Comparison of hepatic artery and portal vein reperfusion during orthotopic liver transplantation [J]. Transplantation, 2001; 72(10): 1680-1684.
11. Vellar ID. The blood supply of the biliary ductal system and its relevance to vasculobiliary injuries following cholecystectomy [J]. Aust N Z J Surg, 1999; 69(11): 816-820.
12. Northover JM, Terblanche J. A new look at the arterial supply of the bile duct in man and its surgical implications [J]. Br J Surg, 1979; 66(6): 379-384.
13. Nishida S, Nakamura N, Kadono J, et al. Intrahepatic biliary strictures after liver transplantation [J]. J Hepatobiliary Pancreat Surg, 2006; 13(6): 511-516.
14. Verdonk RC, Buis CI, Porte RJ, et al. Biliary complications after liver transplantation: a review [J]. Scand J Gastroenterol Suppl, 2006; (243): 89-101.
15. Toledo-Pereyra LH, Toledo AH, Walsh J, et al. Molecular signaling pathways in ischemia/reperfusion [J]. Exp Clin Transplant, 2004; 2(1): 174-177.
16. Wynn TA. Cellular and molecular mechanisms of fibrosis [J]. J Pathol, 2008; 214(2): 199-210.
17. Gran JT, Molberg , Midtvedt . Pathophysiologic aspects of systemic sclerosis [J]. Tidsskr Nor Laegeforen, 2005; 125(19): 2622-2623.
18. 耿智敏，向国安，韩庆，等．转化生长因子β1在胆管愈合过程中的表达及意义 [J]．中国普外基础与临床杂志， 2000； 7（6）： 362-363．.
19. Xu L. Regulation of Smad activities [J]. Biochim Biophys Acta, 2006; 1759(11-12): 503-513.
20. Chen W, Fu X, Sheng Z. Review of current progress in the structure and function of Smad proteins [J]. Chin Med J (Engl), 2002; 115(3): 446-450.
21. Hinz B, Gabbiani G. Cell-matrix and cell-cell contacts of myofibroblasts: role in connective tissue remodeling [J]. Thromb Haemost, 2003; 90(6): 993-1002.
22. Nowak D, Popow-Woz＇niak A, Raz＇nikiewicz L, et al. Actin in the wound healing process [J]. Postepy Biochem, 2009; 55(2): 138-144.
23. Eyden B. The myofibroblast: phenotypic characterization as a prerequisite to understanding its functions in translational medicine [J]. J Cell Mol Med, 2008; 12(1): 22-37.
24. Liu Y. Epithelial to mesenchymal transition in renal fibrogenesis: pathologic significance, molecular mechanism, and therapeutic intervention [J]. J Am Soc Nephrol, 2004; 15(1): 1-12.
25. Zeisberg M, Kalluri R. The role of epithelial-to-mesenchymal transition in renal fibrosis [J]. J Mol Med, 2004; 82(3): 175-181.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Mechanism of Effect of Hepatic Artery Ischemia on Biliary Fibrosis after Liver Transplantation and Prevention Method

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