Inhibition of experimentally-induced liver cirrhosis in rats by a nonpeptidic mimetic of the extracellualr matrix-associated Arg-Gly-Asp epitope |
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Authors: | Rafael Bruck Rami Hershkoviz Ofer Lider Hussein Aeed Liliana Zaider Zipora Matas Jacob Barg Zamir Halpern |
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Institution: | aDepartment of Gastroenterology, E. Wolfson Medical Center, Holon and Sackler School of Medicine, Tel-Aviv University, Weizmann Institute of Science, Rehovot, Israel;bDepartment of Pathology, Sackler School of Medicine, Tel-Aviv University, Weizmann Institute of Science, Rehovot, Israel;cDepartment of Biochemistry, E. Wolfson Medical Center, Holon and Sackler School of Medicine, Tel-Aviv University, Weizmann Institute of Science, Rehovot, Israel;dDepartment of Cell Biology, Weizmann Institute of Science, Rehovot, Israel |
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Abstract: | Aims/Methods: in the present study, we examined whether a nonpeptidic mimetic of Arg-Gly-Asp (RGD), which specifically inhibits RGD-dependent 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 peptide 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 scores than those treated with thioacetamide alone. Further improvement in liver histology was observed after another 8 weeks of treatment with the analogue SF-6,5. Quantitative microscopic analysis by computerized imaging morphometry of liver biopsies from the three groups and controls confirmed the semi-quantitative histopathologic scores (pτ0.001). After 3 months of treatment, the spleen weights in the SF-6,5-treated rats were 30% less than those of rats and that received only thioacetamide, which indicated that the analogue-treated rats were less portal hypertensive.Conclusions: The observed inhibition of the progression of cirrhosis in rats by the nonpeptidic RGD analogue suggests that RGD mimetics may be useful therapeutically in inhibiting pathological processes that involve RGD recognition. |
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Keywords: | Extracellular matrix Fibronectin Liver fibrosis RGD analogue Thioacetamide |
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