Matrix metalloproteinase inhibition protects rat livers from prolonged cold ischemia-warm reperfusion injury
Matrix metalloproteinase inhibition protects rat livers from prolonged cold ischemia-warm reperfusion injury
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DOI：
10.1002/hep.21929
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发表时间：
2008-01-01
期刊：
影响因子：
13.5
通讯作者：
Mari, Bernard
中科院分区：
文献类型：
--
作者：
Defamie, Virginie;Laurens, Marina;Mari, Bernard
基质金属蛋白酶（MMPs）通过改变细胞外基质（ECM）参与冷缺血-热再灌注（CI-WR）后肝损伤，但其确切作用尚不清楚。使用离体灌注的大鼠肝脏，在2种CI条件（4 ℃，24和42小时：存活和非存活肝脏）后，随后进行不同时期的WR，评价肝脏MMP表达。CI-WR诱导肝脏MMP转录水平发生中度变化，不受CI持续时间的影响，而明胶酶活性在肝脏流出物中累积。因此，在将延长的CI RXP 409（10 μ M）加入到威斯康星州大学溶液中后，测试了新的次膦酸MMP抑制剂RXP 409的保护作用，并将肝脏保存42小时（4 ℃），然后在含有20%红细胞的Krebs溶液（37 ℃）中再灌注1小时。记录肝活力参数，并使用台盼蓝核摄取对肝活检评估细胞坏死程度。用RXP 409治疗显著改善肝功能（转氨酶释放和胆汁分泌）和肝损伤。特别地，MMP抑制剂显著改变了细胞死亡的程度，从对照肝脏中发现的坏死肝细胞的大簇（2%-60%的肝脏活组织检查;平均值，26% +/-9%）到处理肝脏中发现的分离的坏死肝细胞（0.2%-12%;平均值，3% +/-2%）（P < 0.05）。结论：这些数据表明，基质金属蛋白酶，通过改变细胞外基质，在肝脏CI-WR损伤，导致广泛的肝细胞坏死中发挥了重要作用，它们的抑制可能被证明是一种新的策略，在改善保存解决方案。
Matrix metalloproteinases (MMPs) have been implicated in the hepatic injury induced after cold ischemia-warm reperfusion (CI-WR), by altering the extracellular matrix (ECM), but their precise role remains unknown. The hepatic MMP expression was evaluated after 2 conditions of CI (4 degrees C for 24 and 42 hours: viable and nonviable livers) followed by different periods of WR, using isolated perfused rat livers. CI-WR induced moderate changes in hepatic MMP transcript levels not influenced by CI duration, whereas gelatinase activities accumulated in liver effluents. Therefore, the protective effect of a new phosphinic MMP inhibitor, RXP409, was tested after prolonged CI RXP409 (10 mu M) was added to the University of Wisconsin solution, and livers were preserved for 42 hours (4 degrees C), then reperfused for 1 hour in Krebs solution (37 degrees C), containing 20% erythrocytes. Liver viability parameters were recorded, and the extent of cell necrosis was evaluated on liver biopsies, using trypan blue nuclear uptake. Treatment with RXP409 significantly improved liver function (transaminase release and bile secretion) and liver injury. In particular, the MMP inhibitor significantly modified the extent of cell death from large dusters of necrotic hepatocytes as found in control livers (2%-60% of liver biopsies; mean, 26% +/- 9%) to isolated necrotic hepatocytes as found in treated livers (0.2%-12%; mean, 3% +/- 2%) (P < 0.05). Conclusion: These data demonstrate that MMPs, by altering the ECM, play a major role in liver CI-WR injury leading to extensive hepatocyte necrosis and that their inhibition might prove to be a new strategy in improving preservation solutions.