中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2018, Vol. 13 ›› Issue (8): 1447-1454.doi: 10.4103/1673-5374.235302

• 原著:脊髓损伤修复保护与再生 • 上一篇    下一篇

基质金属蛋白酶抑制剂降低神经移植和成纤维细胞生长因子1干预脊髓横断大鼠M2巨噬细胞的活性

  

  • 收稿日期:2018-05-26 出版日期:2018-08-15 发布日期:2018-08-15

Local inhibition of matrix metalloproteinases reduced M2 macrophage activity and impeded recovery in spinal cord transected rats after treatment with fibroblast growth factor-1 and nerve grafts.

Chuan-Wen Chiu1, 2, Wen-Hung Huang2, Huai-Sheng Kuo2, May-Jywan Tsai2, Ching-Jung Chen2, Meng-Jen Lee3, Henrich Cheng1, 2, 4   

  1. 1 Department and Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan, China;
    2 Neural Regeneration Laboratory, Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan, China;
    3 Department of Applied Chemistry, Chaoyang University of Technology, Taichung, Taiwan, China;
    4 Center for Neural Regeneration, Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan, China
  • Received:2018-05-26 Online:2018-08-15 Published:2018-08-15
  • Contact: Meng-Jen Lee, Ph.D. or Henrich Cheng, M.D., Ph.D.,mjlee@cyut.edu.tw or hc_cheng@vghtpe.gov.tw.
  • Supported by:

    This work was supported by the National Science Council (102-2320-B-324-001), China. This study was also supported by grants from Taipei Veterans General Hospital (V103E6-001 & V104E6-001) and by grants (MOST 104-2314-B-010-012-MY3, MOST 105-2314-B-010-013-MY2 and MOST 106-2632-B-324-001) from the Ministry of Science and Technology in Taiwan, China.

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摘要：

作者之前的研究表明，周围神经移植物联合成纤维细胞生长因子1治疗可以在脊髓横断的大鼠中招募更多的M2巨噬细胞，并改善功能。实验使用基质金属蛋白酶的抑制剂来影响T8处完全横切大鼠巨噬细胞的迁移，然后检测了巨噬细胞群的迁移和脊髓功能的变化。实验设脊髓横断并移除5mm为T组。接受成纤维细胞生长因子-1和周围神经移植物治疗的脊髓横断大鼠为R组。接受与R组相同的治疗，并给予MMP抑制剂GM6001干预的大鼠为RG组。结果发现，R组的大鼠移植区域中，MMP-9表达上调。局部应用MMP抑制剂导致精氨酸酶-1 /诱导型一氧化氮合酶阳性细胞比率的降低。术后8周应用MMP抑制剂后，R组大鼠恢复的脊髓功能部分丧失。这种效应伴随着神经移植物中脑源性神经营养因子水平的降低。如果联合给药治疗涉及M2募集，则需要考虑同时应用MMP抑制剂还促进MMP活性用于修复损伤脊髓。

orcid:0000-0002-5332-8806(Meng-Jen Lee)
        0000-0001-9393-7422(Henrich Cheng)

 

关键词: 脊髓损伤, 成纤维细胞生长因子-1, 基质金属蛋白酶, GM6001, 巨噬细胞

Abstract:

Alternatively activated macrophages (M2 macrophages) promote central nervous system regeneration. Our previous study demonstrated that treatment with peripheral nerve grafts and fibroblast growth factor-1 recruited more M2 macrophages and improved partial functional recovery in spinal cord transected rats.The migration of macrophages is matrix metalloproteinase (MMP) dependent. We used a general inhibitor of MMPs to influence macrophage migration, and we examined the migration of macrophage populations and changes in spinal function. Rat spinal cords were completely transected at T8, and 5 mm of spinal cord was removed (group T). In group R, spinal cord-transected rats received treatment with fibroblast grow th factor-1 and peripheral nerve grafts. In group RG, rats received the same treatment as group R with the addition of 200 μM GM6001 (an MMP inhibitor) to the fibrin mix. We found that MMP-9, but not MMP-2, was upregulated in the graft area of rats in group R. Local application of the MMP inhibitor resulted in a reduction in the ratio of arginase-1 (M2 macrophage subset)/inducible nitric oxide synthase-postive cells.When the MMP inhibitor was applied at 8 weeks postoperation, the partial functional recovery observed in group R was lost. This effect was accompanied by a decrease in brain-derived neurotrophic factor levels in the nerve graft. These results suggested that the arginase-1 positive population in spinal cord transected rats is a migratory cell population rather than the phenotypic conversion of early iNOS+ cells and that the migration of the arginase-1+ population could be regulated locally. Simultaneous application of MMP inhibitors or promotion of MMP activity for spinal cord injury needs to be considered if the coadministered treatment involves M2 recruitment.

Key words: spinal cord injury, fibroblast growth factor-1, matrix metalloproteinase, GM6001, macrophage