Matrix Metalloproteinase-3 Promotes Early Blood-Spinal Cord Barrier Disruption and Hemorrhage and Impairs Long-Term Neurological Recovery after Spinal Cord Injury

被引:79
作者
Lee, Jee Youn [1 ,2 ]
Choi, Hae Young [1 ,2 ]
Ahn, Hyun-Jong [3 ]
Ju, Bong Gun [5 ]
Yune, Tae Young [1 ,2 ,4 ]
机构
[1] Kyung Hee Univ, Sch Med, Age Related & Brain Dis Res Ctr, Seoul 130701, South Korea
[2] Kyung Hee Univ, Sch Med, Neurodegenerat Control Res Ctr, Seoul 130701, South Korea
[3] Kyung Hee Univ, Sch Med, Dept Microbiol, Seoul 130701, South Korea
[4] Kyung Hee Univ, Sch Med, Dept Biochem & Mol Biol, Seoul 130701, South Korea
[5] Sogang Univ, Dept Life Sci, Seoul, South Korea
关键词
TIGHT JUNCTION PROTEINS; KAPPA-B ACTIVATION; MOTOR-NEURON DEGENERATION; BRAIN-BARRIER; FUNCTIONAL RECOVERY; RAT-BRAIN; NEUTROPHIL INFILTRATION; INFLAMMATORY RESPONSE; CEREBRAL-ISCHEMIA; FOCAL ISCHEMIA;
D O I
10.1016/j.ajpath.2014.07.016
中图分类号
R36 [病理学];
学科分类号
100104 ;
摘要
After spinal cord injury (SCI), blood-spinal cord barrier (BSCB) disruption by matrix metalloproteinases (MMPs) leads to BSCB permeability and blood cell infiltration, contributing to permanent neurological disability. Herein, we report that MMP-3 plays a critical role in BSCB disruption after SCI in mice. MMP-3 was induced in infiltrated neutrophils and blood vessels after SCI, and NF-kappa B as a transcription factor was involved in MMP-3 expression. BSCB permeability and blood cell infiltration after injury were more reduced in Mmp3 knockout (KO) mice than in wild-type (WT) mice, which was significantly inhibited by Mmp3 siRNA or a general inhibitor of MMPs, N-isobutyl-N-(4-methoxyphenylsulfonyl)glycyl hydroxamic acid. The Level of tight junction proteins, such as occludin and zonula occludens-1, which decreased after SCI, was also higher in Mmp3 KO than in WT mice. Exogenously, MMP-3 injection into the normal spinal cord also induced BSCB permeability. Furthermore, MMP-9 activation after injury was mediated by MMP-3 activation. Finally, improved functional recovery was observed in Mmp3 KO mice compared with WT mice after injury. These results demonstrated the role of MMP-3 in BSCB disruption after SCI for the first time and suggest that the regulation of MMP-3 can be considered a therapeutic target to inhibit BSCB disruption and hemorrhage, and thereby enhance functional recovery after acute SCI.
引用
收藏
页码:2985 / 3000
页数:16
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