Myeloperoxidase exacerbates secondary injury by generating highly reactive oxygen species and mediating neutrophil recruitment in experimental spinal cord injury

Kensuke Kubota, Hirokazu Saiwai, Hiromi Kumamaru, Takeshi Maeda, Yasuyuki Ohkawa, Yasuaki Aratani, Tetsuo Nagano, Yukihide Iwamoto, Seiji Okada

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

STUDY DESIGN. An animal study using myeloperoxidase-knockout (MPO-KO) mice to examine the in vivo role of myeloperoxidase (MPO) in spinal cord injury (SCI). OBJECTIVE. To clarify the influence of MPO on inflammatory cell infiltration, tissue damage, and functional recovery after SCI. SUMMARY OF BACKGROUND DATA. MPO is considered to be important in spreading tissue damage after SCI because it generates strong neurotoxic oxidant hypochlorous acid (HOCl). However, the direct involvement of MPO in the pathophysiology of SCI remains to be elucidated. METHODS. To compare the inflammatory reaction, tissue damage, and neurological recovery after SCI, a moderate contusion injury was created at the ninth thoracic level in MPO-KO mice and wild-type mice. A HOCl-specific probe solution was injected into the lesion epicenter to assess the spatiotemporal production of MPO-derived HOCl. Inflammatory reactions were quantified by flow cytometry and quantitative real-time polymerase chain reaction, and tissue damage was evaluated by an immunohistochemical analysis. The motor function recovery was assessed by the open-field locomotor score. RESULTS. Prominent production of HOCl was observed during the hyperacute phase of SCI at the lesion site in the wild-type mice; however, little expression was observed in the MPO-KO mice. In this phase, the number of infiltrated neutrophils was significantly reduced in the MPO-KO mice compared with the wild-type mice. In addition, significant differences were observed in the expression levels of proinflammatory cytokines and apoptosis-related genes between 2 groups. In the histological sections, fewer terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive apoptotic cells and more spared myelin were observed at the lesion site in MPO-KO mice. Consistent with these results, better functional recovery was observed in the MPO-KO mice than in the wild-type mice after SCI. CONCLUSION. These results clearly indicated that MPO exacerbated secondary injury and impaired the functional recovery not only by generating strong oxidant HOCl, but also by enhancing neutrophil infiltration after SCI.

Original languageEnglish
Pages (from-to)1363-1369
Number of pages7
JournalSpine
Volume37
Issue number16
DOIs
Publication statusPublished - Jul 15 2012

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Neutrophil Infiltration
Spinal Cord Injuries
Peroxidase
Reactive Oxygen Species
Wounds and Injuries
Hypochlorous Acid
Knockout Mice
Oxidants
DNA Nucleotidylexotransferase
Contusions
Recovery of Function
Myelin Sheath
Real-Time Polymerase Chain Reaction
Flow Cytometry
Neutrophils
Thorax

All Science Journal Classification (ASJC) codes

  • Orthopedics and Sports Medicine
  • Clinical Neurology

Cite this

Myeloperoxidase exacerbates secondary injury by generating highly reactive oxygen species and mediating neutrophil recruitment in experimental spinal cord injury. / Kubota, Kensuke; Saiwai, Hirokazu; Kumamaru, Hiromi; Maeda, Takeshi; Ohkawa, Yasuyuki; Aratani, Yasuaki; Nagano, Tetsuo; Iwamoto, Yukihide; Okada, Seiji.

In: Spine, Vol. 37, No. 16, 15.07.2012, p. 1363-1369.

Research output: Contribution to journalArticle

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abstract = "STUDY DESIGN. An animal study using myeloperoxidase-knockout (MPO-KO) mice to examine the in vivo role of myeloperoxidase (MPO) in spinal cord injury (SCI). OBJECTIVE. To clarify the influence of MPO on inflammatory cell infiltration, tissue damage, and functional recovery after SCI. SUMMARY OF BACKGROUND DATA. MPO is considered to be important in spreading tissue damage after SCI because it generates strong neurotoxic oxidant hypochlorous acid (HOCl). However, the direct involvement of MPO in the pathophysiology of SCI remains to be elucidated. METHODS. To compare the inflammatory reaction, tissue damage, and neurological recovery after SCI, a moderate contusion injury was created at the ninth thoracic level in MPO-KO mice and wild-type mice. A HOCl-specific probe solution was injected into the lesion epicenter to assess the spatiotemporal production of MPO-derived HOCl. Inflammatory reactions were quantified by flow cytometry and quantitative real-time polymerase chain reaction, and tissue damage was evaluated by an immunohistochemical analysis. The motor function recovery was assessed by the open-field locomotor score. RESULTS. Prominent production of HOCl was observed during the hyperacute phase of SCI at the lesion site in the wild-type mice; however, little expression was observed in the MPO-KO mice. In this phase, the number of infiltrated neutrophils was significantly reduced in the MPO-KO mice compared with the wild-type mice. In addition, significant differences were observed in the expression levels of proinflammatory cytokines and apoptosis-related genes between 2 groups. In the histological sections, fewer terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive apoptotic cells and more spared myelin were observed at the lesion site in MPO-KO mice. Consistent with these results, better functional recovery was observed in the MPO-KO mice than in the wild-type mice after SCI. CONCLUSION. These results clearly indicated that MPO exacerbated secondary injury and impaired the functional recovery not only by generating strong oxidant HOCl, but also by enhancing neutrophil infiltration after SCI.",
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T1 - Myeloperoxidase exacerbates secondary injury by generating highly reactive oxygen species and mediating neutrophil recruitment in experimental spinal cord injury

AU - Kubota, Kensuke

AU - Saiwai, Hirokazu

AU - Kumamaru, Hiromi

AU - Maeda, Takeshi

AU - Ohkawa, Yasuyuki

AU - Aratani, Yasuaki

AU - Nagano, Tetsuo

AU - Iwamoto, Yukihide

AU - Okada, Seiji

PY - 2012/7/15

Y1 - 2012/7/15

N2 - STUDY DESIGN. An animal study using myeloperoxidase-knockout (MPO-KO) mice to examine the in vivo role of myeloperoxidase (MPO) in spinal cord injury (SCI). OBJECTIVE. To clarify the influence of MPO on inflammatory cell infiltration, tissue damage, and functional recovery after SCI. SUMMARY OF BACKGROUND DATA. MPO is considered to be important in spreading tissue damage after SCI because it generates strong neurotoxic oxidant hypochlorous acid (HOCl). However, the direct involvement of MPO in the pathophysiology of SCI remains to be elucidated. METHODS. To compare the inflammatory reaction, tissue damage, and neurological recovery after SCI, a moderate contusion injury was created at the ninth thoracic level in MPO-KO mice and wild-type mice. A HOCl-specific probe solution was injected into the lesion epicenter to assess the spatiotemporal production of MPO-derived HOCl. Inflammatory reactions were quantified by flow cytometry and quantitative real-time polymerase chain reaction, and tissue damage was evaluated by an immunohistochemical analysis. The motor function recovery was assessed by the open-field locomotor score. RESULTS. Prominent production of HOCl was observed during the hyperacute phase of SCI at the lesion site in the wild-type mice; however, little expression was observed in the MPO-KO mice. In this phase, the number of infiltrated neutrophils was significantly reduced in the MPO-KO mice compared with the wild-type mice. In addition, significant differences were observed in the expression levels of proinflammatory cytokines and apoptosis-related genes between 2 groups. In the histological sections, fewer terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive apoptotic cells and more spared myelin were observed at the lesion site in MPO-KO mice. Consistent with these results, better functional recovery was observed in the MPO-KO mice than in the wild-type mice after SCI. CONCLUSION. These results clearly indicated that MPO exacerbated secondary injury and impaired the functional recovery not only by generating strong oxidant HOCl, but also by enhancing neutrophil infiltration after SCI.

AB - STUDY DESIGN. An animal study using myeloperoxidase-knockout (MPO-KO) mice to examine the in vivo role of myeloperoxidase (MPO) in spinal cord injury (SCI). OBJECTIVE. To clarify the influence of MPO on inflammatory cell infiltration, tissue damage, and functional recovery after SCI. SUMMARY OF BACKGROUND DATA. MPO is considered to be important in spreading tissue damage after SCI because it generates strong neurotoxic oxidant hypochlorous acid (HOCl). However, the direct involvement of MPO in the pathophysiology of SCI remains to be elucidated. METHODS. To compare the inflammatory reaction, tissue damage, and neurological recovery after SCI, a moderate contusion injury was created at the ninth thoracic level in MPO-KO mice and wild-type mice. A HOCl-specific probe solution was injected into the lesion epicenter to assess the spatiotemporal production of MPO-derived HOCl. Inflammatory reactions were quantified by flow cytometry and quantitative real-time polymerase chain reaction, and tissue damage was evaluated by an immunohistochemical analysis. The motor function recovery was assessed by the open-field locomotor score. RESULTS. Prominent production of HOCl was observed during the hyperacute phase of SCI at the lesion site in the wild-type mice; however, little expression was observed in the MPO-KO mice. In this phase, the number of infiltrated neutrophils was significantly reduced in the MPO-KO mice compared with the wild-type mice. In addition, significant differences were observed in the expression levels of proinflammatory cytokines and apoptosis-related genes between 2 groups. In the histological sections, fewer terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive apoptotic cells and more spared myelin were observed at the lesion site in MPO-KO mice. Consistent with these results, better functional recovery was observed in the MPO-KO mice than in the wild-type mice after SCI. CONCLUSION. These results clearly indicated that MPO exacerbated secondary injury and impaired the functional recovery not only by generating strong oxidant HOCl, but also by enhancing neutrophil infiltration after SCI.

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