Inhibition of experimentally-induced liver cirrhosis in rats by a nonpeptidic mimetic of the extracellular matrix-associated Arg-Gly-Asp epitope.
OBJECTIVE
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 (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 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.
Bruck
R
R
Department of Gastroenterology, E. Wolfson Medical Center, Holon, Israel.
Hershkoviz
R
R
Lider
O
O
Aeed
H
H
Zaidel
L
L
Matas
Z
Z
Barg
J
J
Halpern
Z
Z
D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001706:Biopsy; D002273:Carcinogens; D002448:Cell Adhesion / Q000187:drug effects; D018450:Disease Progression; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D005353:Fibronectins / Q000187:drug effects / Q000378:metabolism*; D006146:Guanidines / Q000494:pharmacology*; D006439:Hemodynamics; D006975:Hypertension, Portal / Q000473:pathology / Q000503:physiopathology; D008099:Liver / Q000187:drug effects; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D009842:Oligopeptides / Q000737:chemistry; D051381:Rats; D017208:Rats, Wistar; D013154:Spleen / Q000098:blood supply / Q000187:drug effects; D013853:Thioacetamide / Q000633:toxicity; D014631:Valerates / Q000494:pharmacology*
D000970:Antineoplastic Agents; D002273:Carcinogens; D005353:Fibronectins; D006146:Guanidines; D009842:Oligopeptides; D014631:Valerates; D013853:Thioacetamide; C084660:SF 6,5; C047981:arginyl-glycyl-aspartic acid