title: 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.affiliation: Department of Molecular Biology, Flanders Interuniversity Institute for Biotechnology and University of Ghent, Ghent, Belgium.
authors.forename: B
authors.initials: B
authors.lastname: Wielockx
authors.forename: K
authors.initials: K
authors.lastname: Lannoy
authors.forename: S D
authors.initials: SD
authors.lastname: Shapiro
authors.forename: T
authors.initials: T
authors.lastname: Itoh
authors.forename: S
authors.initials: S
authors.lastname: Itohara
authors.forename: J
authors.initials: J
authors.lastname: Vandekerckhove
authors.forename: C
authors.initials: C
authors.lastname: Libert
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D006520:Hepatitis, Animal / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D006801:Humans; D007371:Interferon-gamma / Q000627:therapeutic use / Q000633:toxicity; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000172:deficiency / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009369:Neoplasms / Q000188:drug therapy; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology; D011994:Recombinant Proteins; D013876:Thiophenes / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000627:therapeutic use / Q000633:toxicity
chemical_list: D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D011994:Recombinant Proteins; D013876:Thiophenes; D014409:Tumor Necrosis Factor-alpha; D010649:Phenylalanine; D007371:Interferon-gamma; C080985:batimastat; D020782:Matrix Metalloproteinases