Suppression of proliferative cholangitis in a rat model with direct adenovirus-mediated retinoblastoma gene transfer to the biliary tract

Abstract

Proliferative cholangitis (PC) associated with hepatolithiasis develops the stricture of main bile ducts, and is the main cause of residual and/or recurrent stones after repeated treatments for hepatolithiasis. The aim of this study was to inhibit PC using the cytostatic gene therapy with direct adenovirus-mediated retinoblastoma (Rb) gene transfer to the biliary tract. PC was induced by introducing a fine nylon thread into the bile duct in a rat model. The adenovirus vector encoding a nonphosphorylatable, constitutively active form of retinoblastoma gene product (AdRb) was administered directly into the biliary tract. The adenovirus vector encoding ␤-galactosidase (AdlacZ) was also given as a control. The bile duct wall thickness and 5Ј-bromodeoxyuridine (BrdU) labeling index were compared among uninfected, AdlacZ-infected, and AdRb-infected PC rats. The Rb expression in the bile duct was detected using reversetranscription polymerase chain reaction (RT-PCR) and immunohistochemical study. AdRb-infected bile ducts showed inhibition of the epithelial and fibrous tissue proliferation and the peribiliary gland hyperplasia, resulting in a significant reduction of wall thickness compared with uninfected and AdlacZ-infected ones. The BrdU labeling index was 4.87% ؎ 3.06% in the AdRb-infected bile ducts, while those of uninfected and AdlacZ-infected ones were 15.48% ؎ 4.61% and 11.72% ؎ 1.23%, respectively (P F .05). In conclusion, our cytostatic gene therapy approach using direct Rb gene transfer into the biliary tract suppressed PC in a rat model and may offer an effective therapeutic option for reducing recurrences following treatments against hepatolithiasis. (HEPATOLOGY 1998;28:605-612.)

Reversible Cholestasis and Cholangitis Induced by Biliary Drainage and Infusion in the Rat

“…patchy necrosis, severe neutrophil and lymphocyte infi ltration, and marked bile ductular proliferation. These fi ndings are consistent with the biliary infection observed in other models [19,20] . Few cases of liver fi brosis occurred in this model, but repeated biliary infusions of E. coli would effectively induce recurrent cholangitis.…”

Cirrhotic rat livers with extensive fibrosis can be safely transduced with clinical-grade adenoviral vectors. Evidence of cirrhosis reversion

“…[3][4][5][6][7] Similarly, the use of viral and nonviral vectors for gene delivery to functionally compromised livers has been instrumental to establish 'proof of concept' in several experimental models. Various strategies involving adenoviral vectors have been used.…”

Chemical bile duct embolization for chemical hepatectomy, long term efficacy and feasibility in rats

“…1,18 Calculi in secondary or tertiary subsidiary branches of bile duct are usually complicated with biliary duct stenosis. Therefore, even after successful stone clearance with choledochoscopy, stone recurrence is inevitable.…”

“…5,12 Fu-Yu li, Jing-Qiu Cheng et al 12 suggested that phenol is not only the most efficient sclerosants of gall bladder mucosa, but is also a powerful antiseptic which might not only assist in ameliorating biliary infection which commonly accompanies hepatolithiasis, but also could commendably destroy the biliary mucosa and induced fibrous conglutination in the bile duct lumen, leading to partial occlusion of the large-size and middle-size biliary ducts, and complete occlusion of the small biliary ducts. 18,22,23 However, the biliary system could not be permanently occluded by using phenol or ethanol alone due to the regeneration of biliary mucosa. 22 As an ideal liquid occlusion agent; cyanoacrylate, histoacryl or neoprene has such remarkable liquid-dynamic characteristics that could perfectly fill bile ducts of various sizes, including the acroteric branch.…”