Improved effects of viral gene delivery of human uPA plus biliodigestive anastomosis induce recovery from experimental biliary cirrhosis.
Gene therapy may represent a new avenue for the development of multimodal treatment for diverse forms of cirrhosis. This study explores the potential benefits of combining adenovirus-mediated human urokinase-plasminogen activator (AdHuPA) gene delivery and biliodigestive anastomosis to enhance the therapeutic efficacy of each treatment alone for cholestatic disorders resulting in secondary biliary cirrhosis. In an experimental model of secondary biliary cirrhosis, application of 6 x 10(11) vp/kg AdHuPA adenovirus vector resulted in 25.8% liver fibrosis reduction and some improvement in liver histology. The relief of bile cholestasis by a surgical procedure (biliodigestive anastomosis) combined with AdHuPA hepatic gene delivery rendered a synergistic effect, with a substantial 56.9 to 42.9% fibrosis decrease. AdHuPA transduction resulted in clear-cut expression of human uPA protein detected by immunohistochemistry and induction of up-regulation in the expression of metalloproteinases MMP-3, MMP-9, and MMP-2. Importantly, functional hepatic tests, specifically direct bilirubin, were improved. Also, hepatic cell regeneration, rearrangement of hepatic architecture, ascites, and gastric varices improved in cirrhotic rats treated with AdHuPA but not in counterpart AdGFP cirrhotic animals. We believe this might represent a novel therapeutic strategy for human cholestatic diseases.
Miranda-Díaz
Alejandra
A
Institute of Molecular Biology in Medicine and Gene Therapy, CUCS, University of Guadalajara, Apartado Postal 2-123, 44281, Guadalajara, Jalisco, Mexico.
Rincón
Ana Rosa
AR
Salgado
Silvia
S
Vera-Cruz
José
J
Gálvez
Javier
J
Islas
Ma Cristina
MC
Berumen
Jaime
J
Aguilar-Cordova
Estuardo
E
Armendáriz-Borunda
Juan
J
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D002768:Choledochostomy; D003131:Combined Modality Therapy; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D008099:Liver / Q000201:enzymology; D008105:Liver Cirrhosis, Biliary / Q000473:pathology / Q000601:surgery / Q000628:therapy*; D008115:Liver Regeneration; D045726:Metalloproteases / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D015854:Up-Regulation; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics*
D045726:Metalloproteases; D014568:Urokinase-Type Plasminogen Activator