Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan.
World J Gastroenterol. 2012 May 21;18(19):2320-33. doi: 10.3748/wjg.v18.i19.2320.
To investigate the effect of matrix metalloproteinase-9 (MMP-9) on the remnant liver after massive hepatectomy in the mouse.
Age-matched, C57BL/6 wild-type (WT), MMP-9(-/-), and tissue inhibitors of metalloproteinases (TIMP)-1(-/-) mice were used. The mice received 80%-partial hepatectomy (PH). Samples were obtained at 6 h after 80%-PH, and we used histology, immunohistochemical staining, western blotting analysis and zymography to investigate the effect of PH on MMP-9. The role of MMP-9 after PH was investigated using a monoclonal antibody and MMP inhibitor.
We examined the remnant liver 6 h after 80%-PH and found that MMP-9 deficiency attenuated the formation of hemorrhage and necrosis. There were significantly fewer and smaller hemorrhagic and necrotic lesions in MMP-9(-/-) remnant livers compared with WT and TIMP-1(-/-) livers (P < 0.01), with no difference between WT and TIMP-1(-/-) mice. Serum alanine aminotransaminase levels were significantly lower in MMP-9(-/-) mice compared with those in TIMP-1(-/-) mice (WT: 476 ± 83 IU/L, MMP-9(-/-): 392 ± 30 IU/L, TIMP-1(-/-): 673 ± 73 IU/L, P < 0.01). Western blotting and gelatin zymography demonstrated a lack of MMP-9 expression and activity in MMP-9(-/-) mice, which was in contrast to WT and TIMP-1(-/-) mice. No change in MMP-2 expression was observed in any of the study groups. Similar to MMP-9(-/-) mice, when WT mice were treated with MMP-9 monoclonal antibody or the synthetic inhibitor GM6001, hemorrhagic and necrotic lesions were significantly smaller and fewer than in control mice (P < 0.05). These results suggest that MMP-9 plays an important role in the development of parenchymal hemorrhage and necrosis in the small remnant liver.
Successful MMP-9 inhibition attenuates the formation of hemorrhage and necrosis and might be a potential therapy to ameliorate liver injury after massive hepatectomy.
研究基质金属蛋白酶-9（MMP-9）在小鼠肝大部切除术后残肝中的作用。
使用年龄匹配的 C57BL/6 野生型（WT）、MMP-9（-/-）和基质金属蛋白酶抑制剂（TIMP）-1（-/-）小鼠。小鼠接受 80%部分肝切除术（PH）。在 PH 后 6 小时获取样本，并使用组织学、免疫组织化学染色、Western 印迹分析和明胶酶谱分析来研究 PH 对 MMP-9 的影响。使用单克隆抗体和 MMP 抑制剂研究 PH 后 MMP-9 的作用。
我们检查了 PH 后 80%的残肝 6 小时，发现 MMP-9 缺乏可减轻出血和坏死的形成。与 WT 和 TIMP-1（-/-）肝相比，MMP-9（-/-）残肝的出血和坏死病变明显更少且更小（P < 0.01），WT 和 TIMP-1（-/-）小鼠之间无差异。与 TIMP-1（-/-）小鼠相比，MMP-9（-/-）小鼠的血清丙氨酸氨基转移酶水平明显降低（WT：476 ± 83 IU/L，MMP-9（-/-）：392 ± 30 IU/L，TIMP-1（-/-）：673 ± 73 IU/L，P < 0.01）。Western 印迹和明胶酶谱分析显示 MMP-9（-/-）小鼠缺乏 MMP-9 的表达和活性，与 WT 和 TIMP-1（-/-）小鼠相反。在任何研究组中均未观察到 MMP-2 表达的变化。与 MMP-9（-/-）小鼠相似，当 WT 小鼠用 MMP-9 单克隆抗体或合成抑制剂 GM6001 治疗时，出血和坏死病变明显小于对照组（P < 0.05）。这些结果表明 MMP-9 在小残肝实质出血和坏死的发展中起重要作用。
成功的 MMP-9 抑制可减轻出血和坏死的形成，可能是改善肝大部切除术后肝损伤的潜在治疗方法。
