Metalloproteinase-9 deficiency protects against hepatic ischemia/reperfusion injury
Metalloproteinase-9 deficiency protects against hepatic ischemia/reperfusion injury
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DOI：
10.1002/hep.21922
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发表时间：
2008-01-01
期刊：
影响因子：
13.5
通讯作者：
Coito, Ana J.
中科院分区：
文献类型：
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作者：
Hamada, Takashi;Fondevila, Constantino;Coito, Ana J.
白细胞跨内皮细胞和细胞外基质蛋白屏障的迁移依赖于黏附和局部基质降解事件。在本研究中，我们研究了金属蛋白酶-9(MMP9/明胶酶B)在肝脏缺血/再灌流(I/R)损伤中的作用。方法：用一种特殊的抗MMP9中和抗体或一种广泛的明胶酶抑制剂(MMP2/明胶酶A)处理缺陷型MMP9(-/-)动物和小鼠。与野生型小鼠相比，MMP9(-/-)小鼠和使用抗MMP9抗体治疗的小鼠肝损伤显著减轻。相比之下，使用广泛的明胶酶抑制剂治疗的小鼠对I/R损伤的保护作用较差，并以持续性持续的肝脏炎症为特征，这表明基质金属蛋白酶-2和基质金属蛋白酶-9在这种类型的损伤中可能具有不同的作用。野生型小鼠肝脏I/R损伤后，基质金属蛋白酶-9主要表达于Ly-6G和巨噬细胞抗原-1白细胞，黏附于血管壁并渗入受损的肝脏。在MMP9(-/-)动物和抗MMP9抗体处理的小鼠肝脏I/R损伤后，白细胞转运和细胞因子的表达显著受损；然而，在MMP9-/-和对照肝脏中，内皮黏附级联反应的启动是相似的。我们还发现，在体外，基质金属蛋白酶-9的特异性抑制干扰了中性粒细胞在Transwell滤器中通过纤维连接蛋白的迁移，并抑制了髓过氧化物酶(MPO)的激活。结论：这些结果支持了基质金属蛋白酶-9在白细胞募集和激活导致肝损伤中的重要作用。此外，它们还为寻找体内特异性靶向基质金属蛋白酶-9的抑制剂作为肝I/R损伤的潜在治疗方法提供了理论基础。
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.