ABSTRACT
We have shown that adenosine administration is capable of reversing fibrosis in the carbon tetrachloride-induced rat cirrhotic liver, stimulating the diminished proliferative potential of the cirrhotic liver. To characterize adenosine actions on liver cellular proliferation, we used rats subjected to one-third partial hepatectomy (PH). In PH animals acutely administered with adenosine (25-200 mg/kg b.w.), parameters indicative of cell proliferation were determined. In addition, hepatocyte growth factor (HGF), epidermal growth factor, and transforming growth factor-alpha, cyclins, members of the E2F family, proto-oncogenes, and adenosine-receptors were determined through Western blot analyses. Adenosine (100 mg/kg body weight) induced an earlier increase in liver cell proliferation as evidenced by enhanced levels of proliferating cell nuclear antigen, nuclear Ki-67 antigen, and those for cyclins (D1, E, A, and B1), as well as by an increased mitotic index. These effects were also accompanied for a long-lasting increase of serum and liver levels of HGF and liver expression of c-Met and HGF liver activator. Adenosine effects on cell proliferation could be mediated by an early increase in E2F-1 and by that of c-Myc, despite the fact that phosphorylation of the Rb protein and expression of E2F-3 were decreased. Moreover, the liver amount of specific receptors for adenosine was not significantly changed by PH and/or adenosine treatment. In conclusion, these data suggest that adenosine actions can accelerate and increase proliferation in a "primed" liver, mainly through enhancing c-Myc, E2F family, cell-cycle cyclins, and HGF expression. Therefore, these pharmacological adenosine effects suggest a modulating role for the nucleoside on mitogenic events once the liver has been triggered to proliferate.
