(4-(n-hydroxyamino)-2r-isobutyl-3s-methylsuccinyl)-l-phenylglycine-n-methylamide and Shock--Septic

Hydroxy acid-based matrix metalloproteinase (MMP) inhibitors have been shown to inhibit tumor infiltration and growth, endotoxin shock, and acute graft-versus-host disease. Blockade of the release of soluble tumor necrosis factor-alpha (TNF-alpha) and CD95 ligand (CD95L; FasL) from cell-associated forms is reportedly involved in the mechanism of the drug effect. We investigated the effect of a MMP inhibitor, KB-R7785, on host resistance against Listeria monocytogenes infection, in which TNF-alpha is essentially required for the defense, in mice. The administration of KB-R7785 exacerbated listeriosis, while the drug prevented lethal shock induced by lipopolysaccharide and D-galactosamine. KB-R7785 inhibited soluble TNF-alpha production in spleen cell cultures stimulated by heat-killed L. monocytogenes and the drug treatment reduced serum TNF-alpha levels in infected mice, whereas the compound was ineffective on the modulation of interferon-gamma and interleukin-10 production. The effect of KB-R7785 was considered to be dependent on TNF-alpha because the drug failed to affect L. monocytogenes infection in anti-TNF-alpha monoclonal antibody-treated mice and TNF-alpha knockout mice. Anti-CD95L monoclonal antibody was also ineffective on the infection. These results suggest that induction of infectious diseases, to which TNF-alpha is critical in host resistance, should be considered in MMP inhibitor-treated hosts.

Topics: Animals; Antibodies, Monoclonal; Colony Count, Microbial; Fas Ligand Protein; Female; Glycine; Hydroxamic Acids; Immunity, Innate; Lipopolysaccharides; Listeriosis; Matrix Metalloproteinase Inhibitors; Membrane Glycoproteins; Mice; Mice, Inbred C57BL; Protease Inhibitors; Shock, Septic; Spleen; Tumor Necrosis Factor-alpha

Tumor necrosis factor (TNF) and Fas ligand (FasL) have been implicated in the pathogenesis of graft-versus-host disease (GVHD), which is a major complication after allogeneic bone marrow transplantation. We examined here the ameliorating effect of a metalloproteinase inhibitor (KB-R7785) that inhibits TNF-alpha and FasL release in a lethal acute GVHD model in mice. Administration of KB-R7785 into (BALB/c x C57BL/6) F1 that received C57BL/6 spleen cells markedly reduced the mortality and weight loss in association with minimal signs of GVHD pathology in the liver, intestine, and hematopoietic tissues. The ameliorating effect of KB-R7785 was superior to that of anti-TNF-alpha antibody. Our results suggest that KB-R7785 could be a potent therapeutic agent for GVHD.

Topics: Animals; Crosses, Genetic; Fas Ligand Protein; Female; Glycine; Graft vs Host Disease; Humans; Hydroxamic Acids; Intestines; Lipopolysaccharides; Liver; Lymphocyte Transfusion; Membrane Glycoproteins; Metalloendopeptidases; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Protease Inhibitors; Recombinant Proteins; Shock, Septic; Spleen; Survival Rate; Transfection; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha