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Use of a Hanging-weight System for Liver Ischemia in Mice
Published on: August 7, 2012
Metalloproteinase-9 deficiency protects against hepatic ischemia/reperfusion injury
Takashi Hamada1, Constantino Fondevila, Ronald W Busuttil
1Dumont-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.
Unlabelled:
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.
Insights
Metalloproteinase-9 (MMP-9) plays a critical role in liver ischemia/reperfusion (I/R) injury by mediating leukocyte recruitment and activation. Specific inhibition of MMP-9 reduces liver damage, suggesting its potential as a therapeutic target.
Area of Science:
- Immunology
- Pathophysiology
- Biochemistry
Background:
- Leukocyte transmigration is crucial in inflammatory responses, involving adhesion and matrix degradation.
- Liver ischemia/reperfusion (I/R) injury is a significant clinical challenge with complex inflammatory mechanisms.
Purpose of the Study:
- To investigate the specific role of matrix metalloproteinase-9 (MMP-9) in liver I/R injury.
- To evaluate the therapeutic potential of targeting MMP-9 in this injury model.
Main Methods:
- Utilized MMP-9-deficient mice and specific anti-MMP-9 neutralizing antibodies.
- Administered broad gelatinase inhibitors targeting both MMP-9 and MMP-2.
- Assessed liver damage, leukocyte infiltration, cytokine expression, and neutrophil migration in vitro.
Main Results:
- MMP-9-deficient mice and those treated with anti-MMP-9 showed reduced liver damage.
- Broad gelatinase inhibition offered less protection, indicating distinct roles for MMP-2 and MMP-9.
- MMP-9 inhibition impaired leukocyte traffic and cytokine expression, but not initial endothelial adhesion.
Conclusions:
- MMP-9 is critical for leukocyte recruitment and activation, contributing significantly to liver I/R injury.
- Specific MMP-9 inhibitors represent a promising therapeutic strategy for liver I/R injury.
