INHIBITION OF EXPERIMENTALLY-INDUCED LIVER-CIRRHOSIS IN RATS BY A NONPEPTIDIC MIMETIC OF THE EXTRACELLULAR MATRIX-ASSOCIATED ARG-GLY-ASP EPITOPE

Aims/Methods: In the present study, we examined whether a nonpeptidic mimetic of Arg-Gly-Asp (RGD), which specifically inhibits RGD-dependen t adhesion of CD4(+) T lymphocytes or fibroblasts to fibronectin, can prevent thioacetamide-induced liver cirrhosis in rats. The nonpeptidic RGD mimetic, rather than the RGD peptide was utilized, since the pept ide is rapidly degraded, and therefore, relatively ineffective for in vivo use. Results: We now report that rats treated with thioacetamide and the RGD analogue SF-6,5 for 12 weeks had lower histopathologic sco res than those treated with thioacetamide alone. Further improvement i n liver histology was observed after another 8 weeks of treatment with the analogue SF-6,5. Quantitative microscopic analysis by computerize d imaging morphometry of liver biopsies from the three groups and cont rols confirmed the semi-quantitative histopathologic scores (p<0.001). After 3 months of treatment, the spleen weights in the SF-6,5-treated rats were 30% less than those of rats that received only thioacetamid e, which indicated that the analogue-treated rats were less portal hyp ertensive. Conclusions: The observed inhibition of the progression of cirrhosis in rats by the nonpeptidic RGD analogue suggests that RGD mi metics may be useful therapeutically in inhibiting pathological proces ses that involve RGD recognition.