Metalloproteinase-9 Deficiency Protects Against Hepatic ischemia/reperfusion Injury

Hepatology. 2008 Jan;47(1):186-98. doi: 10.1002/hep.21922.


Leukocyte transmigration across endothelial and extracellular matrix protein barriers is dependent on adhesion and focal matrix degradation events. In the present study we investigated the role of metalloproteinase-9 (MMP-9/gelatinase B) in liver ischemia/reperfusion (I/R) injury using MMP-9-deficient (MMP-9(-/-)) animals and mice treated with a specific anti-MMP-9 neutralizing antibody or with a broad gelatinase inhibitor for both MMP-9 and metalloproteinase-2 (MMP-2/gelatinase A). Compared to wild-type mice, MMP-9(-/-) mice and mice treated with an anti-MMP-9 antibody showed significantly reduced liver damage. In contrast, mice treated with a broad gelatinase inhibitor showed rather inferior protection against I/R injury and were characterized by persistent ongoing liver inflammation, suggesting that MMP-2 and MMP-9 may have distinct roles in this type of injury. MMP-9 was mostly detected in Ly-6G and macrophage antigen-1 leukocytes adherent to the vessel walls and infiltrating the damaged livers of wild-type mice after liver I/R injury. Leukocyte traffic and cytokine expression were markedly impaired in livers of MMP-9(-/-) animals and in livers of mice treated with anti-MMP-9 antibody after I/R injury; however, initiation of the endothelial adhesion cascades was similar in both MMP-9(-/-) and control livers. We also showed that MMP-9-specific inhibition disrupted neutrophil migration across fibronectin in transwell filters and depressed myeloperoxidase (MPO) activation in vitro.

Conclusion: These results support critical functions for MMP-9 in leukocyte recruitment and activation leading to liver damage. Moreover, they provide the rationale for identifying inhibitors to specifically target MMP-9 in vivo as a potential therapeutic approach in liver I/R injury.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies / therapeutic use
  • Cell Movement / physiology
  • Enzyme Inhibitors / therapeutic use
  • Fibronectins / physiology
  • Intercellular Adhesion Molecule-1 / metabolism
  • Leukocytes / physiology
  • Liver Diseases / enzymology*
  • Liver Diseases / immunology
  • Liver Diseases / pathology
  • Liver Diseases / prevention & control
  • Male
  • Matrix Metalloproteinase 9 / deficiency*
  • Matrix Metalloproteinase 9 / immunology
  • Matrix Metalloproteinase Inhibitors*
  • Mice
  • Mice, Knockout
  • Neutrophils / physiology
  • Peroxidase / metabolism
  • Reperfusion Injury / enzymology*
  • Reperfusion Injury / immunology
  • Reperfusion Injury / pathology
  • Reperfusion Injury / prevention & control
  • Vascular Cell Adhesion Molecule-1 / metabolism
  • Warm Ischemia / adverse effects


  • Antibodies
  • Enzyme Inhibitors
  • Fibronectins
  • Matrix Metalloproteinase Inhibitors
  • Vascular Cell Adhesion Molecule-1
  • Intercellular Adhesion Molecule-1
  • Peroxidase
  • Matrix Metalloproteinase 9