Vesnarinone inhibits immune-mediated but not Fas (CD95) agonist-mediated hepatic injury.
Previous studies have shown that the administration of concanavalin A (ConA) into mice induces immune-mediated liver injury, which can be largely abrogated by neutralizing tumor necrosis factor(TNF)alpha. Vesnarinone is an experimental drug which is known to inhibit TNF alpha release. Here we demonstrate that vesnarinone inhibits ConA-induced hepatic injury. In a dose-dependent manner, vesnarinone inhibits in several mouse strains the increase of serum aminotransferase concentrations. additional experiments show that vesnarinone inhibits ConA-mediated accumulation of DNA fragmentation in the liver. Furthermore, the drug significantly reduces the levels of circulating TNF alpha and interleukin-6 (IL-6). Vesnarinone does not modulate TNF alpha and IL-6 action on hepatic cells, as shown by its failure to reduce the cytokine specific-stimulation of acute phase plasma proteins in the rat hepatoma H-35 cell line. Neither vesnarinone nor anti-TNF alpha protect against direct liver injury induced by a sublethal dose of agonist anti-Fas (CD95) antibody. Taken together, these results suggest that vesnarinone blocks hepatic injury, in part by inhibiting the release of TNF alpha in vivo.
Lazarus
D D
DD
Department of Immunology, Otsuka America pharmaceutical Inc., Rockville, MD 20850, USA.
Kambayashi
T
T
Yato-Kioka
M
M
Baumann
H
H
Jacob
C O
CO
Strassmann
G
G
D000210:Acute-Phase Reaction / Q000097:blood / Q000517:prevention & control; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D001327:Autoimmune Diseases / Q000139:chemically induced / Q000276:immunology / Q000517:prevention & control*; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000276:immunology / Q000517:prevention & control*; D003208:Concanavalin A / Q000633:toxicity*; D008114:Liver Neoplasms, Experimental / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011719:Pyrazines; D011804:Quinolines / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000502:physiology*; D019014:fas Receptor / Q000276:immunology / Q000502:physiology*
D000911:Antibodies, Monoclonal; D011719:Pyrazines; D011804:Quinolines; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D003208:Concanavalin A; C041667:vesnarinone