TY - JOUR
T1 - Matrix Metalloproteinase-8 Inhibition Prevents Disruption of Blood–Spinal Cord Barrier and Attenuates Inflammation in Rat Model of Spinal Cord Injury
AU - Kumar, Hemant
AU - Jo, Min Jae
AU - Choi, Hyemin
AU - Muttigi, Manjunatha S.
AU - Shon, Seil
AU - Kim, Byung Joo
AU - Lee, Soo Hong
AU - Han, In Bo
N1 - Funding Information:
Acknowledgments This work was supported by a grant of the National Research Foundation of Korea (NRF) (NRF-2014R1A1A2059118, NRF-2015H1D3A1066543), the Ministry of Science, ICT & Future Planning (NRF-2016R1A2A1A05004987), and the Korea Healthcare Technology Research & Development Project, Ministry for Health & Welfare Affairs, Republic of Korea (HI14C3270, HR16C0002).
Funding Information:
This work was supported by a grant of the National Research Foundation of Korea (NRF) (NRF-2014R1A1A2059118, NRF-2015H1D3A1066543), the Ministry of Science, ICT & Future Planning (NRF-2016R1A2A1A05004987), and the Korea Healthcare Technology Research & Development Project, Ministry for Health & Welfare Affairs, Republic of Korea (HI14C3270, HR16C0002). The authors declare that they have no conflict of interest.
Publisher Copyright:
© 2017, Springer Science+Business Media New York.
PY - 2018/3/1
Y1 - 2018/3/1
N2 - After spinal cord injury (SCI), tight junction (TJ) protein degradation increases permeability and disrupts the blood–spinal cord barrier (BSCB). The BSCB is primarily formed of endothelial cell, which forms a specialized tight seal due to the presence of TJs. BSCB disruption after SCI allows neutrophil infiltration. Matrix metalloproteinase (MMP)-8 is believed to be mainly expressed by neutrophils and is quickly released upon neutrophil activation. Here, we determined whether MMP-8 is involved in the TJ protein degradation in endothelial cells and also determined its role in the neuroinflammation after SCI. MMP-8 recombinant protein treatment increases the TNF-α expression and decreased the TJ (occludin and zonula occludens-1) protein expression in the endothelial cells. Likewise, specific MMP-8 inhibitor (MMP-8I) significantly prevented the TNF-α-induced decrease in the expression of TJ protein in endothelial cells. Furthermore, MMP-8 expression was significantly increased 1 and 3 days after moderate compression (35 g for 5 min at T10 level) SCI, whereas TJ protein levels decreased as determined qRT-PCR, western blotting, and immunohistochemistry. MMP-8 was inhibited directly using a MMP-8I (5 mg/kg) and indirectly by reducing neutrophil infiltration with sivelestat sodium (50 mg/kg) or using the antioxidant N-acetyl-l-cysteine (100 mg/kg). The MMP-8I significantly decreased TNF-α expression, IL-6, and iNOS expression and increased TJ protein expression after SCI. In addition, MMP-8I significantly lessens the amount of Evans blue dye extravasation observed after injury. Thus, our result suggests that MMP-8 plays an imperative role in inflammation and degradation of TJ proteins. Increased MMP-8 expression was associated with the early inflammatory phase of SCI. Inhibiting MMP-8 significantly attenuated SCI-induced inflammation, BSCB breakdown, and cell injury.
AB - After spinal cord injury (SCI), tight junction (TJ) protein degradation increases permeability and disrupts the blood–spinal cord barrier (BSCB). The BSCB is primarily formed of endothelial cell, which forms a specialized tight seal due to the presence of TJs. BSCB disruption after SCI allows neutrophil infiltration. Matrix metalloproteinase (MMP)-8 is believed to be mainly expressed by neutrophils and is quickly released upon neutrophil activation. Here, we determined whether MMP-8 is involved in the TJ protein degradation in endothelial cells and also determined its role in the neuroinflammation after SCI. MMP-8 recombinant protein treatment increases the TNF-α expression and decreased the TJ (occludin and zonula occludens-1) protein expression in the endothelial cells. Likewise, specific MMP-8 inhibitor (MMP-8I) significantly prevented the TNF-α-induced decrease in the expression of TJ protein in endothelial cells. Furthermore, MMP-8 expression was significantly increased 1 and 3 days after moderate compression (35 g for 5 min at T10 level) SCI, whereas TJ protein levels decreased as determined qRT-PCR, western blotting, and immunohistochemistry. MMP-8 was inhibited directly using a MMP-8I (5 mg/kg) and indirectly by reducing neutrophil infiltration with sivelestat sodium (50 mg/kg) or using the antioxidant N-acetyl-l-cysteine (100 mg/kg). The MMP-8I significantly decreased TNF-α expression, IL-6, and iNOS expression and increased TJ protein expression after SCI. In addition, MMP-8I significantly lessens the amount of Evans blue dye extravasation observed after injury. Thus, our result suggests that MMP-8 plays an imperative role in inflammation and degradation of TJ proteins. Increased MMP-8 expression was associated with the early inflammatory phase of SCI. Inhibiting MMP-8 significantly attenuated SCI-induced inflammation, BSCB breakdown, and cell injury.
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U2 - 10.1007/s12035-017-0509-3
DO - 10.1007/s12035-017-0509-3
M3 - Article
C2 - 28421532
AN - SCOPUS:85017592094
SN - 0893-7648
VL - 55
SP - 2577
EP - 2590
JO - Molecular Neurobiology
JF - Molecular Neurobiology
IS - 3
ER -