Adenoviral­bone morphogenetic protein­7 and/or doxazosin therapies promote the reversion of fibrosis/cirrhosis in a cirrhotic hamster model.

ABSTRACT

Liver fibrosis occurs in the presence of continuous insults, including toxic or biological agents. Novel treatments must focus on ceasing the progression of cellular damage, promoting the regeneration of the parenchyma and inhibition of the fibrotic process. The present study analyzed the effect of bone morphogenetic protein (BMP)­7 gene therapy with or without co­treatment with doxazosin in a model of liver cirrhosis in hamsters. The serum alanine aminotransferase, aspartate aminotransferase and albumin levels were analyzed spectrophotometrically. Tissue hepatic samples were analyzed by hematoxylin and eosin for parenchymal structure and Sirius red for collagen fiber content. BMP­7 and α­smooth muscle actin (SMA)­positive cells were detected by immunohistochemistry. BMP­7 and collagen type I content in hepatic tissue were analyzed by western blotting, and tissue inhibitor of metalloproteinases (TIMP)­2 and matrix metalloproteinase (MMP)­13 expression levels were detected by reverse transcription­quantitative polymerase chain reaction. The present study detected a significant reduction of collagen type I deposits in the group treated with adenoviral­transduction with BMP­7 and doxazosin. In animals with BMP­7 and doxazosin therapy, α­SMA­positive cells were 31.7 and 29% significantly decreased compared with animals with placebo, respectively. Adenoviral­BMP­7 transduction and/or doxazosin treatments actively induced decrement in type I collagen deposition via increased MMP­13 and reduced TIMP­2 expression. In conclusion, the adenovirus­BMP­7 gene therapy and the doxazosin therapy are potential candidates for the diminution of fibrosis in the liver, although combination of both therapies does not improve the individual anti­fibrotic effect once cirrhosis is established.