A MATRIX METALLOPROTEINASE INHIBITOR PREVENTS PROCESSING OF TUMOR NECROSIS FACTOR α (TNFα) AND ABROGATES ENDOTOXIN-INDUCED LETHALITY

Abstract

Excessive tumor necrosis factor α (TNFα) production in response to Gram-negative bacteremia or endotoxemia can often lead to hypotension, shock, and increased mortality. Current approaches used to block the deleterious effects of exaggerated TNFα production rely on monoclonal antibodies or immunoadhesins that bind TNFα and thus prevent the interaction with its cellular receptors. This report examines whether a previously described inhibitor of matrix metalloproteinases, GM-6001, can inhibit TNFα processing and release and attenuate endotoxin-induced mortality. In human peripheral blood mononuclear cells stimulated in vitro with 1 μg/mL endotoxin, GM-6001 at concentrations in vivo specificity of this matrix metalloproteinase inhibitor for TNFα processing. These findings demonstrate that a novel inhibitor of matrix metalloproteinases can prevent the release of TNFα both in vitro and in vivo, and can abrogate the harmful sequelae of endotoxemic shock.