Establishment of an early liver fibrosis model by the hydrodynamics-based transfer of TGF-β1 gene

Using our hydrodynamics-based gene transfer model we found that upon induction by ZnSO4, the serum TGF-β1 level in Balb/c mice and Sp1 transcription factor binding activity peaked at 48 h and declined thereafter to a normal level on the 5th day. In addition, mRNA and protein levels of TGF-β1 in the liver were also upregulated at 48 h. Furthermore, induction of TGF-β1 increased the α-smooth muscle actin (α-SMA), p-Smad2/3, hydroxyproline and collagen 1A2 (Col 1A2) levels in the liver, suggesting a significant liver fibrosis.Our results show that TGF-β1 in pPK9a-transferred mice liver with ZnSO4 feeding can achieve a high expression level with significant fibrosis. However, since TGF-β1 induction is transient in our model, the fibrotic level does not reach a large scale (panlobular fibrosis) as seen in the CCl4-treated liver. Our model hence represents a dynamic and reversible liver fibrosis and could be a useful tool for studying early molecular mechanism of fibrogenesis or screening of antifibrotic drugs for clinical use.The development of liver fibrosis, particularly in the cirrhosis stage, is associated with high morbidity and mortality rates [1] and at present the only curative treatment for end stage liver cirrhosis is organ transplantation. The point at which cirrhosis or extensive fibrosis becomes irreversible has not been well defined [2], however, since liver fibrosis is a continuous process in both gene expression and histopathological alterations [3]. Generally accepted animal testing of liver fibrosis includes treatments with hepatotoxins such as carbon tetrachloride (CCl4). However, after the cessation of the long-term treatment of CCl4 for more than 4 weeks, pathological changes in the liver, such as inflammation, are reversed with the exception of fibrosis [3]. Many experimental long-term treatment models of liver fibrosis leading to cirrhosis have been useful for testing drug effectiveness but further studies are required to account for effects of dis