The use of synthetic analogues 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 cholestatic liver diseases, T-lymphocytes serve as effector cells of the immunostimulatory processes. Cellular interactions of immune cells with extracellular matrix (ECM) components are regulated primarily via the beta 1 subfamily of integrin receptors. The target epitope of several such integrin receptors is the Arg-Gly-Asp (RGD) sequence, a cell adhesion motif shared by several matrix-associated adhesive glycoproteins. We review the use of synthetic nonpeptidic analogues of RGD and of soluble receptor of tumor necrosis factor (TNF)-alpha in the prevention of immune-mediated, concanavalin A-induced liver damage in mice and of RGD analogues in inhibiting the development of liver cirrhosis in rats. The concanavalin A-induced elevation of serum transaminases and TNF-alpha, and the infiltration of liver tissue by inflammatory cells, were inhibited by pretreatment of the mice with the synthetic RGD mimetics and soluble TNF receptor. In rats, the progression of thioacetamide-induced liver cirrhosis was markedly inhibited by the coadministration of the RGD mimetic SF-6,5. The compounds described here may be examined therapeutically for pathological conditions in the liver, manifested as necroinflammation, cholestasis and fibrosis.
Bruck
R
R
Department of Gastroenterology, E. Wolfson Medical Center, Holon, Israel.
Hershkoviz
R
R
Lider
O
O
Shirin
H
H
Aeed
H
H
Halpern
Z
Z
D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D004195:Disease Models, Animal; D006146:Guanidines / Q000494:pharmacology; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000293:injuries / Q000378:metabolism; D008106:Liver Cirrhosis, Experimental / Q000517:prevention & control; D008107:Liver Diseases / Q000517:prevention & control*; D051379:Mice; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D018124:Receptors, Tumor Necrosis Factor / Q000737:chemistry / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014631:Valerates / Q000494:pharmacology
D006146:Guanidines; D019012:Integrin beta1; D009842:Oligopeptides; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D014631:Valerates; C084660:SF 6,5; C047981:arginyl-glycyl-aspartic acid