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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Change history
31 October 2018
The original version of the article unfortunately contained an error in funding information. This has been corrected with this erratum.
References
Altman A, Zangan SM. Benign biliary strictures. Semin Intervent Radiol. 2016;33:297–306.
Kaffes AJ. Management of benign biliary strictures: current status and perspective. J Hepatobiliary Pancreat Sci. 2015;22:657–663.
Zepeda-Gomez S, Baron TH. Benign biliary strictures: current endoscopic management. Nat Rev Gastroenterol Hepatol. 2011;8:573–581.
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.
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.
Visrodia KH, Tabibian JH, Baron TH. Endoscopic management of benign biliary strictures. World J Gastrointest Endosc. 2015;7:1003–1013.
Deviere J. Benign biliary strictures and leaks. Gastrointest Endosc Clin N Am. 2015;25:713–723.
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.
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.
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.
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.
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).
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.
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.
Chong T, Fu DL, Li HC, et al. Rapamycin inhibits formation of urethral stricture in rabbits. J Pharmacol Exp Ther. 2011;338:47–52.
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.
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.
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.
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.
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.
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.
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.
Parsi MA. Common controversies in management of biliary strictures. World J Gastroenterol. 2017;23:1119–1124.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Acknowledgments
We thank the China Scholarship Council for funding Ph.D. fellowships to Q.Y. (201706240113). We deeply appreciate the help of language revision by Lennart V. D. Velden, and kind suggestions for improving figures by Xumin Ou.
Funding
This research was supported by the Science and Technology Support Project of Sichuan Province (Nos. 2018SY0019 and 2014SZ0191).
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FL designed this research; JW, HH, FL and CR contributed to the acquisition, analysis and interpretation of the data; QY and WM performed the experimental operation; QY drafted this article; QP and FL revised this manuscript and gave the final approval of the version to be published.
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No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.
Animal care and use
The animal protocol was designed to minimize pain or discomfort to the animals. The animals were acclimatized to laboratory conditions (23 °C, 12 h/12 h/light/dark, 50% humidity, ad libitum access to food and water) for 2 weeks prior to experimentation. Intragastric gavage administration was carried out with conscious animals, using straight gavage needles appropriate for the animal size. All animals were euthanized by barbiturate overdose (intravenous injection, 150 mg/kg pentobarbital sodium) for tissue collection.
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All procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee of the Sichuan University.
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Yang, Q., Wang, J., Liu, F. et al. A Novel Rabbit Model for Benign Biliary Stricture Formation and the Effects of Medication Infusions on Stricture Formation. Dig Dis Sci 63, 2653–2661 (2018). https://doi.org/10.1007/s10620-018-5118-0
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DOI: https://doi.org/10.1007/s10620-018-5118-0