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

Abstract	Acute and fulminant liver failure induced by viral hepatitis, alcohol or other hepatotoxic drugs, are associated with tumor necrosis factor (TNF) production. In a mouse model of lethal hepatitis induced by TNF, apoptosis and necrosis of hepatocytes, but also lethality, hypothermia and influx of leukocytes into the liver, are prevented by a broad-spectrum matrix metalloproteinase (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 findings suggest that several MMPs play a critical role in acute, fulminant hepatitis by degrading the extracellular matrix and allowing massive leukocyte influx in the liver. BB-94 also prevented lethality in TNF/interferon-gamma therapy in tumor-bearing mice. A broad-spectrum MMP inhibitor may be potentially useful for the treatment of patients with acute and perhaps chronic liver failure, and in cancer therapies using inflammatory cytokines.
Authors	B Wielockx, K Lannoy, S D Shapiro, T Itoh, S Itohara, J Vandekerckhove, C Libert
Journal	Nature medicine (Nat Med) Vol. 7 Issue 11 Pg. 1202-8 (Nov 2001) ISSN: 1078-8956 [Print] United States
PMID	11689884 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Matrix Metalloproteinase Inhibitors Protease Inhibitors Recombinant Proteins Thiophenes Tumor Necrosis Factor-alpha Phenylalanine Interferon-gamma batimastat Matrix Metalloproteinases
Topics	Animals Apoptosis (drug effects) Hepatitis, Animal (chemically induced, enzymology, pathology, prevention & control) Humans Interferon-gamma (therapeutic use, toxicity) Matrix Metalloproteinase Inhibitors Matrix Metalloproteinases (deficiency, genetics) Mice Mice, Inbred C57BL Mice, Knockout Neoplasms (drug therapy) Phenylalanine (analogs & derivatives, pharmacology) Protease Inhibitors (pharmacology) Recombinant Proteins Thiophenes (pharmacology) Tumor Necrosis Factor-alpha (therapeutic use, toxicity)

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