Inhibition of matrix metalloproteinases blocks lethal hepatitis and apoptosis induced by tumor necrosis factor and allows safe antitumor therapy

Acute and fulminant liver failure induced by viral hepatitis, alcohol or ot her hepatotoxic drugs, are associated with tumor necrosis factor (TNF) prod uction. In a mouse model of lethal hepatitis induced by TNF, apoptosis and necrosis of hepatocytes, but also lethality, hypothermia and influx of leuk ocytes into the liver, are prevented by a broad-spectrum matrix metalloprot einase (MMP) inhibitor, BB-94. Mice deficient in MMP-2, MMP-3 or MMP-9 had lower levels of apoptosis and necrosis of hepatocytes, and better survival. We found induction of MMP-9 activity and fibronectin degradation. Our find ings suggest that several MMPs play a critical role in acute, fulminant hep atitis by degrading the extracellular matrix and allowing massive leukocyte influx in the liver. BB-94 also prevented lethality in TNF/interferon-gamm a therapy in tumor-bearing mice. A broad-spectrum MMP inhibitor may be pote ntially useful for the treatment of patients with acute and perhaps chronic liver failure, and in cancer therapies using inflammatory cytokines.