Modulation of the secondary injury process after spinal cord injury in Bach1-deficient mice by heme oxygenase-1.
OBJECTIVE
Oxidative stress contributes to secondary injury after spinal cord injury (SCI). The expression of heme oxygenase-1 (HO-1), which protects cells from various insults including oxidative stress, is upregulated in injured spinal cords. Mice deficient in Bach1 (Bach1-/-), a transcriptional repressor of the HO-1 and beta-globin genes, express high levels of HO-1 mRNA and protein in various organs. The authors hypothesized that HO-1 modulates the secondary injury process after SCI in Bach1(-/-) mice.


METHODS
Male C57BL/6 (wild-type) and homozygous Bach1(-/-) C57BL/6 mice were subjected to moderate SCI, and differences in hindlimb motor function, and electrophysiological, molecular biological, and histopathological changes were assessed for 2 weeks.


RESULTS
Functional recovery was greater, and motor evoked potentials were significantly larger in Bach1(-/-) mice than in wild-type mice throughout the observation period. The expression of HO-1 mRNA in the spinal cord was significantly increased in both mice until 3 days after injury, and it was significantly higher in Bach1(-/-) mice than in wild-type mice at every assessment point. Histological examination using Luxol fast blue staining at 1 day after injury showed that the injured areas were smaller in Bach1(-/-) mice than in wild-type mice. The HO-1 immunoreactivity was not detected in uninjured spinal cord, but 3 days postinjury the number of HO-1-immunoreactive cells was obviously higher in the injured area in both mice, particularly in Bach1(-/-) mice. The HO-1 was primarily induced in microglia/macrophage in both mice.


CONCLUSIONS
These results suggest that HO-1 modulates the secondary injury process, and high HO-1 expression may preserve spinal cord function in the early stages after SCI in Bach1(-/-) mice. Treatment that induces HO-1 expression at these early stages may preserve the functional outcome after SCI.
Yamada
Kiyotaka
K
Department of Orthopaedic Surgery, Graduate School of Biomedical Science, Hiroshima University, Hiroshima, Japan. yamada.kiyo@leaf.ocn.ne.jp
Tanaka
Nobuhiro
N
Nakanishi
Kazuyoshi
K
Kamei
Naosuke
N
Ishikawa
Masakazu
M
Mizuno
Toshiyuki
T
Igarashi
Kazuhiro
K
Ochi
Mitsuo
M
D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors / Q000502:physiology*; D004195:Disease Models, Animal; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D006720:Homozygote; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress / Q000502:physiology; D020127:Recovery of Function; D013119:Spinal Cord Injuries / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D013904:Thoracic Vertebrae
C486316:Bach1 protein, mouse; D050976:Basic-Leucine Zipper Transcription Factors; D051547:Heme Oxygenase-1