Experimental Study of Epidermal Growth Factor Receptor Antagonist in Treating Chronic Proliferative Cholangitis_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

ZHOU Yong ¹ , LI Fuyu ¹ , MAO Hui ² , XU Ruihua ¹ , LIU Hong ¹ , ZHANG Yongqiong ¹ , JIANG Ting ¹ , LI Wen ¹ , FENG Yuan ¹ , HAN Qiang. ¹

1.Department of Hepatobiliary Surgery， West China Hospital， Chengdu 610041， Sichuan Province， China;;
2.Department of Respiratory， West China Hospital， Chengdu 610041， Sichuan Province， China;

Corresponding author：

Keywords：

Growth factor receptor antagonist; Hepatolithiasis; Cholangitis; Recurrence; Restenosis

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ObjectiveTo investigate the effectiveness of epidermal growth factor receptor antagonist (AG-1478) on chronic proliferative cholangitis (CPC), so as to investigate new treatment approach for hepatolithiasis associated with CPC. MethodsForty-six SD rats were divided into 5 groups: CPC model group (n=10), only made models. AG-1478 treatment group (divided into 3 mg/kg， 6 mg/kg， and 12 mg/kg groups, n=10 per group), the common bile ducts in CPC animal model received an intralumenal administration of AG-1478 at the meantime of modeling, followed by intraperitoneal AG-1478 injection of 1.5 mg/(kg·d) for 7 days. Sham operation group (SO group, n=6). Subsequently, histopathological observation, immunohistochemistry, real time PCR， and Western blot were used to evaluate the mRNA expression and influence of AG-1478 on the hyperplasia （EGFR， ki-67， BrdU， collagen Ⅰ protein） and lithogenic potential (Mucin 5AC) of CPC. ResultsCompared with CPC model group, the expressions of EGFR, ki-67， and BrdU were obviously decreased in the AG-1478 treatment group. Also, the inhibition of hyperplasia of biliary epithelium and collagen fibers were confirmed by histopathological observation. Additionally, the expressions of Mucin 5AC mRNA and collagen Ⅰ protein remarkable decreased in the AG-1478 treatment group (P lt;0.05). Conclusions EGFR inhibitor (AG-1478) could shows inhibitory effectivenss on the CPC-mediated hyperplasia and lithogenic potential, and therefore holds promise as the new treatment approach for CPC.

Citation： ZHOU Yong,LI Fuyu,MAO Hui,XU Ruihua,LIU Hong,ZHANG Yongqiong,JIANG Ting,LI Wen,FENG Yuan,HAN Qiang.. Experimental Study of Epidermal Growth Factor Receptor Antagonist in Treating Chronic Proliferative Cholangitis. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2011, 18(11): 1155-1159. doi: Copy

1.	AlSukhni W, Gallinger S, Pratzer A, et al. Recurrent pyogenic cholangitis with hepatolithiasis—the role of surgical therapy in North America [J]. J Gastrointest Surg, 2008, 12(3): 496503.
2.	Li FY, Cheng NS, Mao H, et al. Significance of controlling chronic proliferative cholangitis in the treatment of hepatolithiasis [J]. World J Surg, 2009, 33(10): 21552160.
3.	Terada T, Nakanuma Y. Pathologic observations of intrahepatic peribiliary glands in 1 000 consecutive autopsy livers: Ⅳ. Hyperplasia of intramural and extramural glands [J]. Hum Pathol, 1992, 23(5): 483490.
4.	Lu S, Yan L, Rao L, et al. Down stream involvement of the bile duct in hepatolithiasis [J]. Chin Med J, 2002, 115(1): 6264.
5.	Park SM, Choi JW, Kim ST, et al. Suppression of proliferative cholangitis in a rat model by local delivery of paclitaxel [J]. J Hepatobiliary Pancreat Surg, 2003, 10(2): 176182.
6.	Terao R, Honda K, Hatano E, et al. Suppression of proliferative cholangitis in a rat model with direct adenovirusmediated retinoblastoma gene transfer to the biliary tract [J]. Hepatology, 1998, 28(3): 605612.
7.	Kato T, Nishio K. Clinical aspects of epidermal growth factor receptor inhibitors: benefit and risk [J]. Respirology, 2006, 11(6): 693698.
8.	Burgel PR, Nadel JA. Epidermal growth factor receptormediated innate immune responses and their roles in airway diseases [J]. Eur Respir J, 2008, 32(4): 10681081.
9.	Tamaoka M, Hassan M, Mcgovern T, et al. The epidermal growth factor receptor mediates allergic airway remodelling in the rat [J]. Eur Respir J, 2008, 32(5): 12131223.
10.	Takeyama K, Tamaoki J, Kondo M, et al. Role of epidermal growth factor receptor in maintaining airway goblet cell hyperplasia in rats sensitized to allergen [J]. Clin Exp Allergy, 2008, 38(5): 857865.
11.	Nakanuma Y, Yamaguchi K, Ohta G, et al. Pathologic features of hepatolithiasis in Japan [J]. Hum Pathol, 1988, 19(10): 11811186.
12.	Li FY, Cheng JQ, Li N, et al. Effectiveness of chemical biliary duct embolization for chemical hepatectomy [J]. J Gastroenterol Hepatol, 2006, 21(5): 880886.
13.	Yamamoto K. Intrahepatic periductal glands and their significance in primary intrahepatic lithiasis [J]. Jpn J Surg, 1982, 12(3): 163170.
14.	Li F, Cheng J, He S, et al. The practical value of applying chemical biliary duct embolization to chemical hepatectomy for treatment of hepatolithiasis [J]. J Surg Res, 2005, 127(2): 131138.
15.	Burgel PR, Nadel JA. Roles of epidermal growth factor receptor activation in epithelial cell repair and mucin production in airway epithelium [J]. Thorax, 2004, 59(11): 992996.
16.	Hegab AE, Sakamoto T, Nomura A, et al. Niflumic acid and AG1478 reduce cigarette smokeinduced mucin synthesis: the role of hCLCA1 [J]. Chest, 2007, 131(4): 11491156.
17.	Nadel JA. Role of epidermal growth factor receptor activation in regulating mucin synthesis [J]. Respir Res, 2001, 2(2): 8589.
18.	Deshmukh HS, Case LM, Wesselkamper SC, et al. Metalloproteinases mediate mucin 5AC expression by epidermal growth factor receptor activation [J]. Am J Respir Crit Care Med, 2005, 171(4): 305314.
19.	Purdom S, Chen QM. Epidermal growth factor receptordependent and independent pathways in Hydrogen peroxideinduced mitogenactivated protein kinase activation in cardiomyocytes and heart fibroblasts [J]. J Pharmacol Exp Ther, 2005, 312(3): 11791186.
20.	Hardie WD, Davidson C, Ikegami M, et al. EGF receptor tyrosine kinase inhibitors diminish transforming growth factoralphainduced pulmonary fibrosis [J]. Am J Physiol Lung Cell Mol Physiol, 2008, 294(6): L1217L1225.
21.	龙怀聪，王曾礼，肖邦榕，等．酪氨酸激霉抑制剂对哮喘气道重构的影响 [J]．四川大学学报: 医学版， 2005， 36（1）： 3942．.
22.	Ishii Y, Fujimoto S, Fukuda T. Gefitinib prevents bleomycininduced lung fibrosis in mice [J]. Am J Respir Crit Care Med, 2006, 174(5): 550556.
23.	Levitzki A. Tyrosine kinases as targets for cancer therapy [J]. Eur J Cancer, 2002, 38 (Suppl 5): S11S18.

1. AlSukhni W, Gallinger S, Pratzer A, et al. Recurrent pyogenic cholangitis with hepatolithiasis—the role of surgical therapy in North America [J]. J Gastrointest Surg, 2008, 12(3): 496503.
2. Li FY, Cheng NS, Mao H, et al. Significance of controlling chronic proliferative cholangitis in the treatment of hepatolithiasis [J]. World J Surg, 2009, 33(10): 21552160.
3. Terada T, Nakanuma Y. Pathologic observations of intrahepatic peribiliary glands in 1 000 consecutive autopsy livers: Ⅳ. Hyperplasia of intramural and extramural glands [J]. Hum Pathol, 1992, 23(5): 483490.
4. Lu S, Yan L, Rao L, et al. Down stream involvement of the bile duct in hepatolithiasis [J]. Chin Med J, 2002, 115(1): 6264.
5. Park SM, Choi JW, Kim ST, et al. Suppression of proliferative cholangitis in a rat model by local delivery of paclitaxel [J]. J Hepatobiliary Pancreat Surg, 2003, 10(2): 176182.
6. Terao R, Honda K, Hatano E, et al. Suppression of proliferative cholangitis in a rat model with direct adenovirusmediated retinoblastoma gene transfer to the biliary tract [J]. Hepatology, 1998, 28(3): 605612.
7. Kato T, Nishio K. Clinical aspects of epidermal growth factor receptor inhibitors: benefit and risk [J]. Respirology, 2006, 11(6): 693698.
8. Burgel PR, Nadel JA. Epidermal growth factor receptormediated innate immune responses and their roles in airway diseases [J]. Eur Respir J, 2008, 32(4): 10681081.
9. Tamaoka M, Hassan M, Mcgovern T, et al. The epidermal growth factor receptor mediates allergic airway remodelling in the rat [J]. Eur Respir J, 2008, 32(5): 12131223.
10. Takeyama K, Tamaoki J, Kondo M, et al. Role of epidermal growth factor receptor in maintaining airway goblet cell hyperplasia in rats sensitized to allergen [J]. Clin Exp Allergy, 2008, 38(5): 857865.
11. Nakanuma Y, Yamaguchi K, Ohta G, et al. Pathologic features of hepatolithiasis in Japan [J]. Hum Pathol, 1988, 19(10): 11811186.
12. Li FY, Cheng JQ, Li N, et al. Effectiveness of chemical biliary duct embolization for chemical hepatectomy [J]. J Gastroenterol Hepatol, 2006, 21(5): 880886.
13. Yamamoto K. Intrahepatic periductal glands and their significance in primary intrahepatic lithiasis [J]. Jpn J Surg, 1982, 12(3): 163170.
14. Li F, Cheng J, He S, et al. The practical value of applying chemical biliary duct embolization to chemical hepatectomy for treatment of hepatolithiasis [J]. J Surg Res, 2005, 127(2): 131138.
15. Burgel PR, Nadel JA. Roles of epidermal growth factor receptor activation in epithelial cell repair and mucin production in airway epithelium [J]. Thorax, 2004, 59(11): 992996.
16. Hegab AE, Sakamoto T, Nomura A, et al. Niflumic acid and AG1478 reduce cigarette smokeinduced mucin synthesis: the role of hCLCA1 [J]. Chest, 2007, 131(4): 11491156.
17. Nadel JA. Role of epidermal growth factor receptor activation in regulating mucin synthesis [J]. Respir Res, 2001, 2(2): 8589.
18. Deshmukh HS, Case LM, Wesselkamper SC, et al. Metalloproteinases mediate mucin 5AC expression by epidermal growth factor receptor activation [J]. Am J Respir Crit Care Med, 2005, 171(4): 305314.
19. Purdom S, Chen QM. Epidermal growth factor receptordependent and independent pathways in Hydrogen peroxideinduced mitogenactivated protein kinase activation in cardiomyocytes and heart fibroblasts [J]. J Pharmacol Exp Ther, 2005, 312(3): 11791186.
20. Hardie WD, Davidson C, Ikegami M, et al. EGF receptor tyrosine kinase inhibitors diminish transforming growth factoralphainduced pulmonary fibrosis [J]. Am J Physiol Lung Cell Mol Physiol, 2008, 294(6): L1217L1225.
21. 龙怀聪，王曾礼，肖邦榕，等．酪氨酸激霉抑制剂对哮喘气道重构的影响 [J]．四川大学学报: 医学版， 2005， 36（1）： 3942．.
22. Ishii Y, Fujimoto S, Fukuda T. Gefitinib prevents bleomycininduced lung fibrosis in mice [J]. Am J Respir Crit Care Med, 2006, 174(5): 550556.
23. Levitzki A. Tyrosine kinases as targets for cancer therapy [J]. Eur J Cancer, 2002, 38 (Suppl 5): S11S18.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Experimental Study of Epidermal Growth Factor Receptor Antagonist in Treating Chronic Proliferative Cholangitis

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