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 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.
Wielockx
B
B
Department of Molecular Biology, Flanders Interuniversity Institute for Biotechnology and University of Ghent, Ghent, Belgium.
Lannoy
K
K
Shapiro
S D
SD
Itoh
T
T
Itohara
S
S
Vandekerckhove
J
J
Libert
C
C
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
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