Adenovirus-mediated p53 gene transfer to the bile duct by direct administration into the bile in a rat cholangitis model

Background. Hepatolithiasis is a common disease in East Asia and its aggravating factor is bile duct stenosis because of refractory cholangitis. This study investigated the feasibility of gene therapy for bile duct stenosis by administration of p53 adenoviral vectors into the bile. Materials and methods. Adenoviral vectors (AxCALacZ or AxCAhp53) were injected transpapillarily into the bile in the bile duct in a rat model of cholangitis. The extent and duration of the gene expression was evaluated with X-gal staining and p53 immunostaining. The bile duct tissue was examined to evaluate the inhibitory effect on the proliferative changes at 3 and 7 days after administration, and Ki-67 labeling index was determined. Results. beta-galactosidase was expressed in the bile duct epithelia, the bile duct wall and the surrounding connective tissue. The expression of P-galactosidase was detected at 4 weeks after the administration. Mean thickness of the bile duct wall at 7 days was 343.2 +/- 14.0 mu m for the AxCAhp53 group, 446.5 +/- 25.3 mu m for the AxCALacZ group and 447.1 +/- 53.4 mu m for the control group. The proliferation of the bile duct wall was significantly suppressed in the AxCAhp53 group (P < 0.05). Maximum thickness was 408.0 +/- 23.9 mu m for the AxCAhp53 group (P < 0.05), 650.0 +/- 49.3 mu m for the AxCALacZ group, and 590.0 +/- 64.3 mu m for the control group. Mean Ki-67 labeling index for the three groups was 20.7% (P < 0.05), 34.4% and 37.4%, respectively. Conclusions. P53 gene transfer by administration of the adenoviral vector into the bile suppressed the proliferative changes in the bile duct in a rat cholangitis model. (c) 2005 Elsevier Inc. All rights reserved.