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Published in: Digestive Diseases and Sciences 10/2018

01-10-2018 | Original Article

A Novel Rabbit Model for Benign Biliary Stricture Formation and the Effects of Medication Infusions on Stricture Formation

Authors: Qin Yang, Junke Wang, Fei Liu, Wenjie Ma, Haijie Hu, Congdun Ran, Fuyu Li, Qiuwei Pan

Published in: Digestive Diseases and Sciences | Issue 10/2018

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Abstract

Background

Benign biliary stricture (BBS) is highly refractory. Currently, there is no effective strategy for prevention of BBS recurrence. The aim of this study is to establish a novel BBS rabbit model and to investigate the efficacy of biliary infusion with anti-proliferative medications for treating BBS.

Method

A BBS model was established via surgical injury and biliary infection. The biliary infusion tube was inserted into the common bile duct via the stump of cystic duct after cholecystectomy. Biliary infusions with Rapamycin, Pirfenidone and Fasudil were performed daily during the 4 weeks following the surgery. The wall thickness and luminal area of the bile duct were assessed.

Results

All rabbits formed BBS after surgery. The mortality rate was 13% (8/60) and tube withdrawal rate was 4% (2/48). The thickness of the bile duct wall was significantly reduced; whereas the luminal area of the bile duct was dramatically enlarged in the Rapamycin or the Pirfenidone treated group, compared to the saline treated group. Furthermore, the local treatment significantly decreased the levels of proliferation makers, including PCNA, Collagen I and fibrogenic mediators, including ACTA2 and TGF-beta.

Conclusion

We have established a novel animal model for BBS formation. We have further demonstrated that biliary infusion with Rapamycin or Pirfenidone limits the biliary strictures through inhibiting the proliferation of the bile duct wall in this model. This may represent a new avenue for preventing biliary restenosis.
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Literature
1.
go back to reference Altman A, Zangan SM. Benign biliary strictures. Semin Intervent Radiol. 2016;33:297–306.CrossRef Altman A, Zangan SM. Benign biliary strictures. Semin Intervent Radiol. 2016;33:297–306.CrossRef
2.
go back to reference Kaffes AJ. Management of benign biliary strictures: current status and perspective. J Hepatobiliary Pancreat Sci. 2015;22:657–663.CrossRef Kaffes AJ. Management of benign biliary strictures: current status and perspective. J Hepatobiliary Pancreat Sci. 2015;22:657–663.CrossRef
3.
go back to reference Zepeda-Gomez S, Baron TH. Benign biliary strictures: current endoscopic management. Nat Rev Gastroenterol Hepatol. 2011;8:573–581.CrossRef Zepeda-Gomez S, Baron TH. Benign biliary strictures: current endoscopic management. Nat Rev Gastroenterol Hepatol. 2011;8:573–581.CrossRef
4.
go back to reference Hu B, Sun B, Cai Q, et al. Asia-Pacific consensus guidelines for endoscopic management of benign biliary strictures. Gastrointest Endosc. 2017;86:44–58.CrossRef Hu B, Sun B, Cai Q, et al. Asia-Pacific consensus guidelines for endoscopic management of benign biliary strictures. Gastrointest Endosc. 2017;86:44–58.CrossRef
5.
go back to reference Mauri G, Michelozzi C, Melchiorre F, et al. Benign biliary strictures refractory to standard bilioplasty treated using polydoxanone biodegradable biliary stents: retrospective multicentric data analysis on 107 patients. Eur Radiol. 2016;26:4057–4063.CrossRef Mauri G, Michelozzi C, Melchiorre F, et al. Benign biliary strictures refractory to standard bilioplasty treated using polydoxanone biodegradable biliary stents: retrospective multicentric data analysis on 107 patients. Eur Radiol. 2016;26:4057–4063.CrossRef
6.
go back to reference Visrodia KH, Tabibian JH, Baron TH. Endoscopic management of benign biliary strictures. World J Gastrointest Endosc. 2015;7:1003–1013.CrossRef Visrodia KH, Tabibian JH, Baron TH. Endoscopic management of benign biliary strictures. World J Gastrointest Endosc. 2015;7:1003–1013.CrossRef
7.
go back to reference Deviere J. Benign biliary strictures and leaks. Gastrointest Endosc Clin N Am. 2015;25:713–723.CrossRef Deviere J. Benign biliary strictures and leaks. Gastrointest Endosc Clin N Am. 2015;25:713–723.CrossRef
8.
go back to reference Weber A, Zellner S, Wagenpfeil S, et al. Long-term follow-up after endoscopic stent therapy for benign biliary strictures. J Clin Gastroenterol. 2014;48:88–93.CrossRef Weber A, Zellner S, Wagenpfeil S, et al. Long-term follow-up after endoscopic stent therapy for benign biliary strictures. J Clin Gastroenterol. 2014;48:88–93.CrossRef
9.
go back to reference Geng ZM, Yao YM, Liu QG, Niu XJ, Liu XG. Mechanism of benign biliary stricture: a morphological and immunohistochemical study. World J Gastroenterol. 2005;11:293–295.CrossRef Geng ZM, Yao YM, Liu QG, Niu XJ, Liu XG. Mechanism of benign biliary stricture: a morphological and immunohistochemical study. World J Gastroenterol. 2005;11:293–295.CrossRef
10.
go back to reference Li FY, Cheng NS, Mao H, et al. Significance of controlling chronic proliferative cholangitis in the treatment of hepatolithiasis. World J Surg. 2009;33:2155–2160.CrossRef Li FY, Cheng NS, Mao H, et al. Significance of controlling chronic proliferative cholangitis in the treatment of hepatolithiasis. World J Surg. 2009;33:2155–2160.CrossRef
11.
go back to reference Li KY, Shi CX, Huang JZ, Tang KL. Tetramethylpyrazine effects on the expression of scar-related genes in rabbit benign biliary stricture fibroblasts. J Coll Physicians Surg Pak. 2016;26:813–817.PubMed Li KY, Shi CX, Huang JZ, Tang KL. Tetramethylpyrazine effects on the expression of scar-related genes in rabbit benign biliary stricture fibroblasts. J Coll Physicians Surg Pak. 2016;26:813–817.PubMed
12.
go back to reference Liu YK, Li ZH, Liu NZ, et al. Reduced myoelectric activity in the sphincter of Oddi in a new model of chronic cholangitis in rabbits: an in vivo and in vitro study. Neurogastroenterol Motil. 2010;22(8):927–934. (e238–e929).CrossRef Liu YK, Li ZH, Liu NZ, et al. Reduced myoelectric activity in the sphincter of Oddi in a new model of chronic cholangitis in rabbits: an in vivo and in vitro study. Neurogastroenterol Motil. 2010;22(8):927–934. (e238–e929).CrossRef
13.
go back to reference Sievert KD, Selent-Stier C, Wiedemann J, et al. Introducing a large animal model to create urethral stricture similar to human stricture disease: a comparative experimental microscopic study. J Urol. 2012;187:1101–1109.CrossRef Sievert KD, Selent-Stier C, Wiedemann J, et al. Introducing a large animal model to create urethral stricture similar to human stricture disease: a comparative experimental microscopic study. J Urol. 2012;187:1101–1109.CrossRef
14.
go back to reference Lim KS, Park JK, Jeong MH, et al. Effect of stents coated with a combination of sirolimus and alpha-lipoic acid in a porcine coronary restenosis model. J Mater Sci Mater Med. 2016;27:66.CrossRef Lim KS, Park JK, Jeong MH, et al. Effect of stents coated with a combination of sirolimus and alpha-lipoic acid in a porcine coronary restenosis model. J Mater Sci Mater Med. 2016;27:66.CrossRef
15.
go back to reference Chong T, Fu DL, Li HC, et al. Rapamycin inhibits formation of urethral stricture in rabbits. J Pharmacol Exp Ther. 2011;338:47–52.CrossRef Chong T, Fu DL, Li HC, et al. Rapamycin inhibits formation of urethral stricture in rabbits. J Pharmacol Exp Ther. 2011;338:47–52.CrossRef
16.
go back to reference Yamaguchi Y, Feghali-Bostwick CA. Role of endostatin in fibroproliferative disorders.-as a candidate for anti-fibrosis therapy. Jpn J Clin Immunol. 2013;36:452–458.CrossRef Yamaguchi Y, Feghali-Bostwick CA. Role of endostatin in fibroproliferative disorders.-as a candidate for anti-fibrosis therapy. Jpn J Clin Immunol. 2013;36:452–458.CrossRef
17.
go back to reference Stahnke T, Kowtharapu BS, Stachs O, et al. Suppression of TGF-beta pathway by pirfenidone decreases extracellular matrix deposition in ocular fibroblasts in vitro. PLoS ONE. 2017;12:e0172592.CrossRef Stahnke T, Kowtharapu BS, Stachs O, et al. Suppression of TGF-beta pathway by pirfenidone decreases extracellular matrix deposition in ocular fibroblasts in vitro. PLoS ONE. 2017;12:e0172592.CrossRef
18.
go back to reference Hasdemir PS, Ozkut M, Guvenal T, et al. Effect of pirfenidone on vascular proliferation, inflammation and fibrosis in an abdominal adhesion rat model. J Investig Surg. 2017;30:26–32.CrossRef Hasdemir PS, Ozkut M, Guvenal T, et al. Effect of pirfenidone on vascular proliferation, inflammation and fibrosis in an abdominal adhesion rat model. J Investig Surg. 2017;30:26–32.CrossRef
19.
go back to reference Olmos-Zuniga JR, Silva-Martinez M, Jasso-Victoria R, et al. Effects of pirfenidone and collagen-polyvinylpyrrolidone on macroscopic and microscopic changes, TGF-beta1 expression, and collagen deposition in an experimental model of tracheal wound healing. Biomed Res Int. 2017;2017:6471071.CrossRef Olmos-Zuniga JR, Silva-Martinez M, Jasso-Victoria R, et al. Effects of pirfenidone and collagen-polyvinylpyrrolidone on macroscopic and microscopic changes, TGF-beta1 expression, and collagen deposition in an experimental model of tracheal wound healing. Biomed Res Int. 2017;2017:6471071.CrossRef
20.
go back to reference Orozco-Perez J, Aguirre-Jauregui O, Salazar-Montes AM, Sobrevilla-Navarro AA, Lucano-Landeros MS, Armendariz-Borunda J. Pirfenidone prevents rat esophageal stricture formation. J Surg Res. 2015;194:558–564.CrossRef Orozco-Perez J, Aguirre-Jauregui O, Salazar-Montes AM, Sobrevilla-Navarro AA, Lucano-Landeros MS, Armendariz-Borunda J. Pirfenidone prevents rat esophageal stricture formation. J Surg Res. 2015;194:558–564.CrossRef
21.
go back to reference Zhang K, Guo X, Zhao W, Niu G, Mo X, Fu Q. Application of Wnt pathway inhibitor delivering scaffold for inhibiting fibrosis in urethra strictures. In vitro and in vivo study. Int J Mol Sci. 2015;16:27659–27676.CrossRef Zhang K, Guo X, Zhao W, Niu G, Mo X, Fu Q. Application of Wnt pathway inhibitor delivering scaffold for inhibiting fibrosis in urethra strictures. In vitro and in vivo study. Int J Mol Sci. 2015;16:27659–27676.CrossRef
22.
go back to reference Shenkar R, Shi C, Austin C, et al. RhoA kinase inhibition with Fasudil versus simvastatin in murine models of cerebral cavernous malformations. Stroke. 2017;48:187–194.CrossRef Shenkar R, Shi C, Austin C, et al. RhoA kinase inhibition with Fasudil versus simvastatin in murine models of cerebral cavernous malformations. Stroke. 2017;48:187–194.CrossRef
23.
go back to reference Parsi MA. Common controversies in management of biliary strictures. World J Gastroenterol. 2017;23:1119–1124.CrossRef Parsi MA. Common controversies in management of biliary strictures. World J Gastroenterol. 2017;23:1119–1124.CrossRef
24.
go back to reference Komiya C, Tanaka M, Tsuchiya K, et al. Antifibrotic effect of pirfenidone in a mouse model of human nonalcoholic steatohepatitis. Sci Rep. 2017;7:44754.CrossRef Komiya C, Tanaka M, Tsuchiya K, et al. Antifibrotic effect of pirfenidone in a mouse model of human nonalcoholic steatohepatitis. Sci Rep. 2017;7:44754.CrossRef
25.
go back to reference Du J, Paz K, Flynn R, et al. Pirfenidone ameliorates murine chronic GVHD through inhibition of macrophage infiltration and TGF-beta production. Blood. 2017;129:2570–2580.CrossRef Du J, Paz K, Flynn R, et al. Pirfenidone ameliorates murine chronic GVHD through inhibition of macrophage infiltration and TGF-beta production. Blood. 2017;129:2570–2580.CrossRef
26.
go back to reference Wu YH, Li XW, Li WQ, et al. Fluorofenidone attenuates bleomycin-induced pulmonary fibrosis by inhibiting eukaryotic translation initiation factor 3a (eIF3a) in rats. Eur J Pharmacol. 2016;773:42–50.CrossRef Wu YH, Li XW, Li WQ, et al. Fluorofenidone attenuates bleomycin-induced pulmonary fibrosis by inhibiting eukaryotic translation initiation factor 3a (eIF3a) in rats. Eur J Pharmacol. 2016;773:42–50.CrossRef
27.
go back to reference Shen C, Peng C, Shen B, et al. Sirolimus and metformin synergistically inhibit hepatocellular carcinoma cell proliferation and improve long-term survival in patients with HCC related to hepatitis B virus induced cirrhosis after liver transplantation. Oncotarget. 2016;7:62647–62656.PubMedPubMedCentral Shen C, Peng C, Shen B, et al. Sirolimus and metformin synergistically inhibit hepatocellular carcinoma cell proliferation and improve long-term survival in patients with HCC related to hepatitis B virus induced cirrhosis after liver transplantation. Oncotarget. 2016;7:62647–62656.PubMedPubMedCentral
28.
go back to reference Li G, Ren J, Hu Q, et al. Oral pirfenidone protects against fibrosis by inhibiting fibroblast proliferation and TGF-beta signaling in a murine colitis model. Biochem Pharmacol. 2016;117:57–67.CrossRef Li G, Ren J, Hu Q, et al. Oral pirfenidone protects against fibrosis by inhibiting fibroblast proliferation and TGF-beta signaling in a murine colitis model. Biochem Pharmacol. 2016;117:57–67.CrossRef
29.
go back to reference Chen LP, Zhang QH, Chen G, Qian YY, Shi BY, Dong JH. Rapamycin inhibits cholangiocyte regeneration by blocking interleukin-6-induced activation of signal transducer and activator of transcription 3 after liver transplantation. Liver Transpl. 2010;16:204–214.CrossRef Chen LP, Zhang QH, Chen G, Qian YY, Shi BY, Dong JH. Rapamycin inhibits cholangiocyte regeneration by blocking interleukin-6-induced activation of signal transducer and activator of transcription 3 after liver transplantation. Liver Transpl. 2010;16:204–214.CrossRef
30.
go back to reference Chen C, Yu JZ, Zhang Q, et al. Role of Rho Kinase and Fasudil on synaptic plasticity in multiple sclerosis. NeuroMol Med. 2015;17:454–465.CrossRef Chen C, Yu JZ, Zhang Q, et al. Role of Rho Kinase and Fasudil on synaptic plasticity in multiple sclerosis. NeuroMol Med. 2015;17:454–465.CrossRef
31.
go back to reference Bond JE, Kokosis G, Ren L, Selim MA, Bergeron A, Levinson H. Wound contraction is attenuated by Fasudil inhibition of Rho-associated kinase. Plast Reconstr Surg. 2011;128:438e–450e.CrossRef Bond JE, Kokosis G, Ren L, Selim MA, Bergeron A, Levinson H. Wound contraction is attenuated by Fasudil inhibition of Rho-associated kinase. Plast Reconstr Surg. 2011;128:438e–450e.CrossRef
32.
go back to reference Wang L, Wang T, Song M, Pan J. Rho plays a key role in TGF-beta1-induced proliferation and cytoskeleton rearrangement of human periodontal ligament cells. Arch Oral Biol. 2014;59:149–157.CrossRef Wang L, Wang T, Song M, Pan J. Rho plays a key role in TGF-beta1-induced proliferation and cytoskeleton rearrangement of human periodontal ligament cells. Arch Oral Biol. 2014;59:149–157.CrossRef
Metadata
Title
A Novel Rabbit Model for Benign Biliary Stricture Formation and the Effects of Medication Infusions on Stricture Formation
Authors
Qin Yang
Junke Wang
Fei Liu
Wenjie Ma
Haijie Hu
Congdun Ran
Fuyu Li
Qiuwei Pan
Publication date
01-10-2018
Publisher
Springer US
Published in
Digestive Diseases and Sciences / Issue 10/2018
Print ISSN: 0163-2116
Electronic ISSN: 1573-2568
DOI
https://doi.org/10.1007/s10620-018-5118-0

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