表皮生長因子受體拮抗劑對慢性增生性膽管炎的實驗療效探討_《中國普外基礎與臨床雜志》

作者：

周勇 ¹ , 李富宇 ¹ , 毛輝 ² , 徐瑞華 ¹ , 劉紅 ¹ , 張永瓊 ¹ , 江婷 ¹ , 李玟 ¹ , 馮媛 ¹ , 韓薔 ¹

1.四川大學華西醫院肝膽外科(四川成都 610041);;
2.四川大學華西醫院呼吸內科(四川成都 610041);

關鍵詞：

表皮生長因子受體拮抗劑肝內膽管結石膽管炎復發膽管狹窄

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目的探討表皮生長因子受體（EGFR）拮抗劑能否抑制慢性增生性膽管炎（CPC）的過度增殖行為和成石潛力，以期為肝內膽管結石的防治探索新的治療途徑。方法將46只健康SD大鼠隨機分為5組： CPC模型組（10只），僅行造模處理； 3種劑量EGFR拮抗劑AG-1478治療組（分為3 mg/kg、6 mg/kg和12 mg/kg組，各10只），在行造模術的同時經膽總管內注入相應劑量的AG-1478，術后7 d內腹腔內注射AG-1478 1.5 mg/（kg·d）；假手術組（SO組，6只），僅行開腹術后即關腹。于術后7 d剖腹取膽管標本組織分別行病理組織學觀察、免疫組化染色、RT-PCR和Western blot檢測，比較各組EGFR、5-溴脫氧尿核苷（BrdU）、Ki-67、黏蛋白5AC 和Ⅰ型膠原蛋白的mRNA或蛋白表達情況，以評估AG-1478對病變膽管黏膜過度增殖行為（EGFR、Ki-67、BrdU、Ⅰ型膠原蛋白）和成石潛力(黏蛋白5AC)的影響。結果與CPC模型組比較，治療組的EGFR、Ki-67及BrdU表達明顯降低，組織學觀察所見的膽管黏膜上皮和膠原纖維的過度增殖行為也得到了有效的抑制；此外，治療組的黏蛋白5AC mRNA和Ⅰ型膠原蛋白表達水平也較CPC模型組明顯降低(P lt;0.05)。結論EGFR拮抗劑可有效抑制CPC病變膽管黏膜的過度增殖和成石潛力，有望成為CPC新的治療手段。

引用本文： 周勇,李富宇,毛輝,徐瑞華,劉紅,張永瓊,江婷,李玟,馮媛,韓薔. 表皮生長因子受體拮抗劑對慢性增生性膽管炎的實驗療效探討. 中國普外基礎與臨床雜志, 2011, 18(11): 1155-1159. doi: 復制

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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.	龍懷聰，王曾禮，肖邦榕，等．酪氨酸激霉抑制劑對哮喘氣道重構的影響 [J]．四川大學學報: 醫學版， 2005， 36（1）： 3942．.
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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. 龍懷聰，王曾禮，肖邦榕，等．酪氨酸激霉抑制劑對哮喘氣道重構的影響 [J]．四川大學學報: 醫學版， 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.

《中國普外基礎與臨床雜志》

表皮生長因子受體拮抗劑對慢性增生性膽管炎的實驗療效探討

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《中國普外基礎與臨床雜志》

表皮生長因子受體拮抗劑對慢性增生性膽管炎的實驗療效探討

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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