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Neutrophil elastase inhibition effectively rescued angiopoietin-1 decrease and inhibits glial scar after spinal cord injury

After spinal cord injury (SCI), neutrophil elastase (NE) released at injury site disrupts vascular endothelium integrity and stabilization. Angiopoietins (ANGPTs) are vascular growth factors that play an important role in vascular stabilization. We hypothesized that neutrophil elastase is one of the...

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Autores principales: Kumar, Hemant, Choi, Hyemin, Jo, Min-Jae, Joshi, Hari Prasad, Muttigi, Manjunatha, Bonanomi, Dario, Kim, Sung Bum, Ban, Eunmi, Kim, Aeri, Lee, Soo-Hong, Kim, Kyoung-Tae, Sohn, Seil, Zeng, Xiang, Han, Inbo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6080383/
https://www.ncbi.nlm.nih.gov/pubmed/30086801
http://dx.doi.org/10.1186/s40478-018-0576-3
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author Kumar, Hemant
Choi, Hyemin
Jo, Min-Jae
Joshi, Hari Prasad
Muttigi, Manjunatha
Bonanomi, Dario
Kim, Sung Bum
Ban, Eunmi
Kim, Aeri
Lee, Soo-Hong
Kim, Kyoung-Tae
Sohn, Seil
Zeng, Xiang
Han, Inbo
author_facet Kumar, Hemant
Choi, Hyemin
Jo, Min-Jae
Joshi, Hari Prasad
Muttigi, Manjunatha
Bonanomi, Dario
Kim, Sung Bum
Ban, Eunmi
Kim, Aeri
Lee, Soo-Hong
Kim, Kyoung-Tae
Sohn, Seil
Zeng, Xiang
Han, Inbo
author_sort Kumar, Hemant
collection PubMed
description After spinal cord injury (SCI), neutrophil elastase (NE) released at injury site disrupts vascular endothelium integrity and stabilization. Angiopoietins (ANGPTs) are vascular growth factors that play an important role in vascular stabilization. We hypothesized that neutrophil elastase is one of the key determinants of vascular endothelium disruption/destabilization and affects angiopoietins expression after spinal cord injury. To test this, tubule formation and angiopoietins expression were assessed in endothelial cells exposed to different concentrations of recombinant neutropil elastase. Then, the expression of angiopoietin-1, angiopoietin-2, and neutrophil elastase was determined at 3 h and at 1, 3, 5, 7, 14, 21, and 28 days in a clinically relevant model of moderate compression (35 g for 5 min at T10) spinal cord injury. A dichotomy between the levels of angiopoietin-1 and angiopoietin-2 was observed; thus, we utilized a specific neutrophil elastase inhibitor (sivelestat sodium; 30 mg/kg, i.p., b.i.d.) after spinal cord injury. The expression levels of neutropil elastase and angiopoietin-2 increased, and that of angiopoietin-1 decreased after spinal cord injury in rats. The sivelestat regimen, optimized via a pharmacokinetics study, had potent effects on vascular stabilization by upregulating angiopoietin-1 via the AKT pathway and preventing tight junction protein degradation. Moreover, sivelestat attenuated the levels of inflammatory cytokines and chemokines after spinal cord injury and hence subsequently alleviated secondary damage observed as a reduction in glial scar formation and the promotion of blood vessel formation and stabilization. As a result, hindlimb locomotor function significantly recovered in the sivelestat-treated animals as determined by the Basso, Beattie, and Bresnahan scale and footprint analyses. Furthermore, sivelestat treatment attenuated neuropathic pain as assessed by responses to von Frey filaments after spinal cord injury. Thus, our result suggests that inhibiting neutropil elastase by administration of sivelestat is a promising therapeutic strategy to inhibit glial scar and promote functional recovery by upregulating angiopoietin-1 after spinal cord injury. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s40478-018-0576-3) contains supplementary material, which is available to authorized users.
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spelling pubmed-60803832018-08-09 Neutrophil elastase inhibition effectively rescued angiopoietin-1 decrease and inhibits glial scar after spinal cord injury Kumar, Hemant Choi, Hyemin Jo, Min-Jae Joshi, Hari Prasad Muttigi, Manjunatha Bonanomi, Dario Kim, Sung Bum Ban, Eunmi Kim, Aeri Lee, Soo-Hong Kim, Kyoung-Tae Sohn, Seil Zeng, Xiang Han, Inbo Acta Neuropathol Commun Research After spinal cord injury (SCI), neutrophil elastase (NE) released at injury site disrupts vascular endothelium integrity and stabilization. Angiopoietins (ANGPTs) are vascular growth factors that play an important role in vascular stabilization. We hypothesized that neutrophil elastase is one of the key determinants of vascular endothelium disruption/destabilization and affects angiopoietins expression after spinal cord injury. To test this, tubule formation and angiopoietins expression were assessed in endothelial cells exposed to different concentrations of recombinant neutropil elastase. Then, the expression of angiopoietin-1, angiopoietin-2, and neutrophil elastase was determined at 3 h and at 1, 3, 5, 7, 14, 21, and 28 days in a clinically relevant model of moderate compression (35 g for 5 min at T10) spinal cord injury. A dichotomy between the levels of angiopoietin-1 and angiopoietin-2 was observed; thus, we utilized a specific neutrophil elastase inhibitor (sivelestat sodium; 30 mg/kg, i.p., b.i.d.) after spinal cord injury. The expression levels of neutropil elastase and angiopoietin-2 increased, and that of angiopoietin-1 decreased after spinal cord injury in rats. The sivelestat regimen, optimized via a pharmacokinetics study, had potent effects on vascular stabilization by upregulating angiopoietin-1 via the AKT pathway and preventing tight junction protein degradation. Moreover, sivelestat attenuated the levels of inflammatory cytokines and chemokines after spinal cord injury and hence subsequently alleviated secondary damage observed as a reduction in glial scar formation and the promotion of blood vessel formation and stabilization. As a result, hindlimb locomotor function significantly recovered in the sivelestat-treated animals as determined by the Basso, Beattie, and Bresnahan scale and footprint analyses. Furthermore, sivelestat treatment attenuated neuropathic pain as assessed by responses to von Frey filaments after spinal cord injury. Thus, our result suggests that inhibiting neutropil elastase by administration of sivelestat is a promising therapeutic strategy to inhibit glial scar and promote functional recovery by upregulating angiopoietin-1 after spinal cord injury. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s40478-018-0576-3) contains supplementary material, which is available to authorized users. BioMed Central 2018-08-07 /pmc/articles/PMC6080383/ /pubmed/30086801 http://dx.doi.org/10.1186/s40478-018-0576-3 Text en © The Author(s). 2018 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Kumar, Hemant
Choi, Hyemin
Jo, Min-Jae
Joshi, Hari Prasad
Muttigi, Manjunatha
Bonanomi, Dario
Kim, Sung Bum
Ban, Eunmi
Kim, Aeri
Lee, Soo-Hong
Kim, Kyoung-Tae
Sohn, Seil
Zeng, Xiang
Han, Inbo
Neutrophil elastase inhibition effectively rescued angiopoietin-1 decrease and inhibits glial scar after spinal cord injury
title Neutrophil elastase inhibition effectively rescued angiopoietin-1 decrease and inhibits glial scar after spinal cord injury
title_full Neutrophil elastase inhibition effectively rescued angiopoietin-1 decrease and inhibits glial scar after spinal cord injury
title_fullStr Neutrophil elastase inhibition effectively rescued angiopoietin-1 decrease and inhibits glial scar after spinal cord injury
title_full_unstemmed Neutrophil elastase inhibition effectively rescued angiopoietin-1 decrease and inhibits glial scar after spinal cord injury
title_short Neutrophil elastase inhibition effectively rescued angiopoietin-1 decrease and inhibits glial scar after spinal cord injury
title_sort neutrophil elastase inhibition effectively rescued angiopoietin-1 decrease and inhibits glial scar after spinal cord injury
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6080383/
https://www.ncbi.nlm.nih.gov/pubmed/30086801
http://dx.doi.org/10.1186/s40478-018-0576-3
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