Metalloproteinase-9 deficiency protects against hepatic ischemia/reperfusion injury.
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.


CONCLUSIONS
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.
Hamada
Takashi
T
Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA 90095-7054, USA.
Fondevila
Constantino
C
Busuttil
Ronald W
RW
Coito
Ana J
AJ
D000818:Animals; D000906:Antibodies / Q000627:therapeutic use; D002465:Cell Movement / Q000502:physiology; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005353:Fibronectins / Q000502:physiology; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007962:Leukocytes / Q000502:physiology; D008107:Liver Diseases / Q000201:enzymology* / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000172:deficiency* / Q000276:immunology; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000502:physiology; D009195:Peroxidase / Q000378:metabolism; D015427:Reperfusion Injury / Q000201:enzymology* / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D052096:Warm Ischemia / Q000009:adverse effects
D000906:Antibodies; D004791:Enzyme Inhibitors; D005353:Fibronectins; D061965:Matrix Metalloproteinase Inhibitors; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D009195:Peroxidase; D020780:Matrix Metalloproteinase 9