THE USE OF SYNTHETIC ANALOGS OF ARG-GLY-ASP (RGD) AND SOLUBLE RECEPTOR OF TUMOR-NECROSIS-FACTOR TO PREVENT ACUTE AND CHRONIC EXPERIMENTAL LIVER-INJURY

In chronic viral hepatitis, autoimmune hepatitis, and some chronic cho lestatic liver diseases, T-lymphocytes serve as effector cells of the immunostimulatory processes. Cellular interactions of immune cells wit h extracellular matrix (ECM) components are regulated primarily via th e beta 1 subfamily of integrin receptors. The target epitope of severa l such integrin receptors is the Arg-Gly-Asp (RGD) sequence, a cell ad hesion motif shared by several matrix-associated adhesive glycoprotein s. We review the use of synthetic nonpeptidic analogues of RGD and of soluble receptor of tumor necrosis factor (TNF)-alpha in the preventio n of immune-mediated, concanavalin A-induced liver damage in mice and of RGD analogues in inhibiting the development of liver cirrhosis in r ats. The concanavalin A-induced elevation of serum transaminases and T NF-alpha, and the infiltration of liver tissue by inflammatory cells, were inhibited by pretreatment of the mice with the synthetic RGD mime tics and soluble TNF receptor. In rats, the progression of thioacetami de-induced liver cirrhosis was markedly inhibited by the coadministrat ion of the RGD mimetic SF-6,5. The compounds described here may be exa mined therapeutically for pathological conditions in the liver, manife sted as necroinflammation, cholestasis and fibrosis.