Metalloproteinase-9 deficiency protects against hepatic ischemia/reperfusion injury

被引:119
作者
Hamada, Takashi [1 ]
Fondevila, Constantino [1 ]
Busuttil, Ronald W. [1 ]
Coito, Ana J. [1 ]
机构
[1] Dumont Univ Calif Los Angeles, Transplant Ctr, David Geffen Sch Med, Dept Surg,Div Liver & Pancreas Transplantat, Los Angeles, CA 90095 USA
关键词
D O I
10.1002/hep.21922
中图分类号
R57 [消化系及腹部疾病];
学科分类号
摘要
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.
引用
收藏
页码:186 / 198
页数:13
相关论文
共 50 条
[1]   Polarization and directed migration of murine neutrophils is dependent on cell surface expression of CD44 [J].
Alstergren, P ;
Zhu, BQ ;
Glougauer, M ;
Mak, TW ;
Ellen, RP ;
Sodek, J .
CELLULAR IMMUNOLOGY, 2004, 231 (1-2) :146-157
[2]   Fibronectin-α4β1 integrin-mediated blockade protects genetically fat Zucker rat livers from ischemia/reperfusion injury [J].
Amersi, F ;
Shen, XD ;
Moore, C ;
Melinek, J ;
Busuttil, RW ;
Kupiec-Weglinski, JW ;
Coito, AJ .
AMERICAN JOURNAL OF PATHOLOGY, 2003, 162 (04) :1229-1239
[3]   Focalized proteolysis: Spatial and temporal regulation of extracellular matrix degradation at the cell surface [J].
Basbaum, CB ;
Werb, Z .
CURRENT OPINION IN CELL BIOLOGY, 1996, 8 (05) :731-738
[4]   Through and beyond the wall: late steps in leukocyte transendothelial migration [J].
Bianchi, E ;
Bender, JR ;
Blasi, F ;
Pardi, R .
IMMUNOLOGY TODAY, 1997, 18 (12) :586-591
[5]   Matrix metalloproteinase-9 deficiency impairs cellular infiltration and bronchial hyperresponsiveness during allergen-induced airway inflammation [J].
Cataldo, DD ;
Tournoy, KG ;
Vermaelen, K ;
Munaut, C ;
Foidart, JM ;
Louis, R ;
Noël, A ;
Pauwels, RA .
AMERICAN JOURNAL OF PATHOLOGY, 2002, 161 (02) :491-498
[6]  
COITO AJ, 1995, J IMMUNOL, V154, P2949
[7]  
Coito AJ, 1997, AM J PATHOL, V150, P1757
[8]   New functions for the matrix metalloproteinases in cancer progression [J].
Egeblad, M ;
Werb, Z .
NATURE REVIEWS CANCER, 2002, 2 (03) :161-174
[9]   Formation of nitric oxide derived inflammatory oxidants by myeloperoxidase in neutrophils [J].
Eiserich, JP ;
Hristova, M ;
Cross, CE ;
Jones, AD ;
Freeman, BA ;
Halliwell, B ;
van der Vliet, A .
NATURE, 1998, 391 (6665) :393-397
[10]  
Ellis TN, 2002, J LEUKOCYTE BIOL, V72, P373