A Novel Rabbit Model for Benign Biliary Stricture Formation and the Effects of Medication Infusions on Stricture Formation
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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.
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.
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.
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.
KeywordsBenign biliary stricture Animal model Biliary infusion Local anti-proliferation Recurrence
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.
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.
This research was supported by the Science and Technology Support Project of Sichuan Province (Nos. 2018SY0019 and 2014SZ0191).
Compliance with ethical standards
Conflict of interest
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.
Institutional animal care and use committee
All procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee of the Sichuan University.
- 19.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.CrossRefGoogle Scholar
- 27.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.PubMedPubMedCentralGoogle Scholar