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-γ 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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Bernal, W. & Wendon, J. Acute liver failure; clinical features and management. Eur. J. Gastroenterol. Hepatol. 11, 977–984 (1999).
Marcellin, P. Hepatitis C: The clinical spectrum of the disease. J. Hepatol. 31, 9–16 (1999).
Hoofnagle, J.H., Carithers, R.L. Jr, Shapiro, C. & Ascher, N. Fulminant hepatic failure: summary of a workshop. Hepatology. 21, 240–252 (1995).
Gonzalez–Amaro, R. et al. Induction of tumor necrosis factor α production by human hepatocytes in chronic viral hepatitis. J. Exp. Med. 179, 841–848 (1994).
Bird, G.L.A., Sheron, N., Goka, J., Alexander, G.J. & Williams, R.S. Increased plasma tumor necrosis factor in severe alcoholic hepatitis. Ann. Intern. Med. 112, 917–920 (1990).
Muto, Y. et al. Enhanced tumour necrosis factor and interleukin-1 in fulminant hepatic failure. Lancet 8602, 72–74 (1988).
Kowdley, K.V. TNF-α in chronic hepatitis C: The smoking gun? Am. J. Gastroenterol. 94, 1132–1135 (1999).
Beyaert, R. & Fiers, W. Tumor necrosis factor and lymphotoxin. in Cytokines. (eds. Mire-Sluis, A.R. & Thorpe, R.) 335–360 (Academic Press, San Diego, 1998).
Fransen, L., Ruysschaert, M.R., Van der Heyden, J. & Fiers, W. Recombinant tumor necrosis factor: species specificity for a variety of human and murine transformed cell lines. Cell. Immunol. 100, 260–267 (1986).
Brouckaert, P.G.G., Leroux–Roels, G.G., Guisez, Y., Tavernier, J. & Fiers, W. In vivo anti-tumour activity of recombinant human and murine TNF, alone and in combination with murine IFN-gamma, on a syngeneic murine melanoma. Int. J. Cancer 38, 763–769 (1986).
Leist, M., Gantner, F., Jilg, S. & Wendel, A. Activation of the 55 kDa TNF receptor is necessary and sufficient for TNF-induced liver failure, hepatocyte apoptosis, and nitrite release. J. Immunol. 154,1307–1316 (1995)
Iimuro, Y., Gallucci, R.M., Luster, M.I., Kono, H. & Thurman, R.G. Antibodies to tumor necrosis factor α attenuate hepatic necrosis and inflammation caused by chronic exposure to ethanol in the rat. Hepatology 26, 1530–1537 (1997).
Brennan, F.M. et al. Reduction of serum matrix metalloproteinase 1 and matrix metalloproteinase 3 in rheumatoid arthritis patients following anti-tumour necrosis factor-α (cA2) therapy. Br. J. Rheumat. 36, 643–650 (1997).
Rajavashisth, T.B. et al. Membrane type 1 matrix metalloproteinase expression in human atherosclerotic plaques: evidence for activation by proinflammatory mediators. Circulation 99, 3103–3109 (1999).
Holmbeck, K. et al. MT1-MMP-deficient mice develop dwarfism, osteopenia, arthritis, and connective tissue disease due to inadequate collagen turnover. Cell 99, 81–92 (1999).
Vu, T.H. et al. MMP-9/gelatinase B is a key regulator of growth plate angiogenesis and apoptosis of hypertrophic chondrocytes. Cell 93, 411–422 (1998).
Shapiro, S.D. Matrix metalloproteinase degradation of extracellular matrix: Biological consequences. Curr. Opin. Cell. Biol. 10, 602–608 (1998).
Lund, L.R. et al. Functional overlap between two classes of matrix-degrading proteases in wound healing. EMBO J. 18, 4645–4656 (1999).
Lochter, A., Sternlicht M.D., Werb, Z. & Bissell, M.J. The significance of matrix metalloproteinases during early stages of tumor progression. Ann. NY Acad. Sci. 857, 180–193 (1998).
Hautamaki, R.D., Kobayashi, D.K., Senior, R.M. & Shapiro, S.D. Requirement for macrophage elastase for cigarette smoke-induced emphysema in mice. Science 277, 2002–2004 (1997).
Knittel, T. et al. Expression patterns of matrix metalloproteinases and their inhibitors in parenchymal and non-parenchymal cells of rat liver: Regulation by TNF-α and TGF-β1. J. Hepatol. 30, 48–60 (1999).
Decker, K. & Keppler, D. Galactosamine hepatitis: key role of the nucleotide deficiency period in the pathogenesis of cell injury and cell death. Rev. Physiol. Biochem. Pharmacol. 71, 77–106 (1974).
Koivunen, E. et al. Tumor targeting with a selective gelatinase inhibitor. Nature Biotechnol. 17, 768–774 (1999).
Jaeschke, H., Farhood, A. & Smith, W. Neutrophil-induced liver cell injury in endotoxin shock is a CD11b/CD18-dependent mechanism. Am. J. Physiol. 261, 1051–1056 (1991).
Shiratori, Y. et al. Role of endotoxin-responsive macrophages in hepatic injury. Hepatology 11, 183–192 (1990).
Sternlicht, M.D. et al. The stromal proteinase MMP3/stromelysin-1 promotes mammary carcinogenesis. Cell 98, 137–146 (1999).
Carmeliet, P. et al. Urokinase-generated plasmin activates matrix metalloproteinases during aneurysm formation. Nature Genet. 17, 439–444 (1997).
Alexander, R.B. & Rosenberg, S.A. Tumor necrosis factor: clinical applications. in Biologic Therapy of Cancer. (eds. DeVita, V.T. Jr, Hellman, S. & Rosenberg, S.A) 378–392 (J.B. Lippincott, Philadelphia, 1991).
Libert, C., Brouckaert, P. & Fiers, W. Protection by α1-acid glycoprotein against tumor necrosis factor-induced lethality. J. Exp. Med. 180, 1571–1575 (1994).
Skotnicki, J.S. et al. Design and synthetic considerations of matrix metalloproteinase inhibitors. Ann NY Acad. Sci. 878, 61–72 (1999).
Yamamoto, M. et al. Inhibition of membrane-type 1 matrix metalloproteinase by hydroxamate inhibitors: An examination of the subsite pocket. J. Med. Chem. 41, 1209–1217 (1998).
Giavazzi, R. et al. Batimastat, a synthetic inhibitor of matrix metalloproteinases, potentiates the antitumor activity of cisplatin in ovarian carcinoma xenografts. Clin. Cancer Res. 4, 985–992 (1998).
Arthur, M.J.P. Fibrogenesis II. Metalloproteinases and their inhibitors in liver fibrosis. Am. J. Physiol. Gastrointest. Liver Physiol. 279, 245–249 (2000).
Takenaka, K., Sakaida, I., Yasunaga, M. & Okita, K. Ultrastructural study of development of hepatic necrosis induced by TNF-α and d-galactosamine. Dig. Dis. Sci. 43, 887–892 (1998).
Pugin, J. et al. Human neutrophils secrete gelatinase B in vitro and in vivo in response to endotoxin and proinflammatory mediators. Am. J. Respir. Cell. Mol. Biol. 20, 458–464 (1999).
Martinez-Hernandez, A. & Amenta, P.S. The hepatic extracellular matrix. Virchows Archiv. A Pathol. Anat. 423, 1–11 (1993).
Amour, A. et al. Inhibition of the metalloproteinase domain of mouse TACE. Ann. NY Acad. Sci. 878, 728–731 (1999).
Gearing, A.J. et al. Processing of tumour necrosis factor-α precursor by metalloproteinases. Nature 370, 555–557 (1994).
Yu, Q. & Stamenkovic, I. Cell surface-localized matrix metalloproteinase-9 proteolytically activates TGF-β and promotes tumor invasion and angiogenesis. Genes Dev. 14, 163–176 (2000).
Schonbeck, U., Mach, F. & Libby P. Generation of biologically active IL-1β by matrix metalloproteinases: a novel caspase-1-independent pathway of IL-1β processing. J. Immunol. 161, 3340–3346 (1998).
Murdoch, W.J. Plasmin-tumour necrosis factor interaction in the ovulatory process. J. Reprod. Fertil. Suppl. 54, 353–358 (1999).
Lochter, A. et al. Matrix metalloproteinase stromelysin-1 triggers a cascade of molecular alterations that leads to stable epithelial-to-mesenchymal conversion and a premalignant phenotype in mammary epithelial cells. J. Cell Biol. 139, 1861–1872 (1997).
Libert, C. et al. Response of interleukin-6–deficient mice to tumor necrosis factor-induced metabolic changes and lethality. Eur. J. Immunol. 24, 2237–2242 (1994).
Everaerdt, B., Brouckaert, P. & Fiers, W. A recombinant interleukin-1 receptor antagonist protects against tumor necrosis factor-induced lethality in mice. J. Immunol. 152, 5041–5049 (1994).
Itoh, T. et al. Unaltered secretion of β-amyloid precursor protein in gelatinase A (matrix metalloproteinase 2)-deficient mice. J. Biol. Chem. 272, 22389–22392 (1997).
Mudgett, J.S. et al. Susceptibility of stromelysin 1-deficient mice to collagen-induced arthritis and cartilage destruction. Arthritis Rheum. 41, 110–121 (1998).
Shipley, J.M., Wesselschmidt, R.L., Kobayashi, D.K., Ley, T.J. & Shapiro, S.D. Metalloelastase is required for macrophage-mediated proteolysis and matrix invasion in mice. Proc. Natl. Acad. Sci. USA 93, 3942–3946 (1996).
Van Molle, W., C. Libert, W. Fiers & Brouckaert, P. α1-Acid glycoprotein and α1-antitrypsin inhibit TNF-induced but not anti-Fas-induced apoptosis of hepatocytes in mice. J. Immunol. 159, 3555–3561 (1997).
Van Molle, W. et al. Activation of caspases in lethal experimental hepatitis and prevention by acute phase proteins. J. Immunol. 163, 5235–5241 (1999).
Acknowledgements
We thank F. Duerinck for preparing recombinant TNF; J. Vanden Berghe, L. Puimège, L. Van Geert, M. Goessens and E. Spruyt for excellent technical assistance; M. Goethals for preparing cyclic decapeptide; L. Moons for providing anti-MMP-9 antibody; British Biotech for MMP inhibitor; and J.S. Mudgett for MMP-3-deficient mice. This work was supported by the Interuniversitaire Attractiepolen and the Fonds voor Wetenschappelijk Onderzoek–Vlaanderen.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Wielockx, B., Lannoy, K., Shapiro, S. et al. Inhibition of matrix metalloproteinases blocks lethal hepatitis and apoptosis induced by tumor necrosis factor and allows safe antitumor therapy. Nat Med 7, 1202–1208 (2001). https://doi.org/10.1038/nm1101-1202
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/nm1101-1202
This article is cited by
-
Using the inbred mouse strain SPRET/EiJ to provide novel insights in inflammation and infection research
Mammalian Genome (2018)
-
Aptamer-miRNA-212 Conjugate Sensitizes NSCLC Cells to TRAIL
Molecular Therapy - Nucleic Acids (2016)
-
BLT1 signalling protects the liver against acetaminophen hepatotoxicity by preventing excessive accumulation of hepatic neutrophils
Scientific Reports (2016)
-
Association of endothelin-1 and matrix metallopeptidase-9 with metabolic syndrome in middle-aged and older adults
Diabetology & Metabolic Syndrome (2015)
-
Cultured mycelium Cordyceps sinensis protects liver sinusoidal endothelial cells in acute liver injured mice
Molecular Biology Reports (2014)