Heme oxygenase-1 stabilizes the blood-spinal cord barrier and limits oxidative stress and white matter damage in the acutely injured murine spinal cord

J Cereb Blood Flow Metab. 2007 May;27(5):1010-21. doi: 10.1038/sj.jcbfm.9600412. Epub 2006 Oct 18.

Abstract

We hypothesized that heme oxygenase (HO)-1, the inducible form of HO, represents an important defense against early oxidative injury in the traumatized spinal cord by stabilizing the blood-spinal cord barrier and limiting the infiltration of leukocytes. To test this hypothesis, we first examined the immunoexpression of HO-1 and compared barrier permeability and leukocyte infiltration in spinal cord-injured HO-1-deficient (+/-) and wild-type (WT, +/+) mice. Heme oxygenase was expressed in both endothelial cells and glia of the injured cord. Barrier disruption to luciferase and infiltration of neutrophils were significantly greater in the HO-1+/- than WT mice at 24 h postinjury (P<or=0.019 and =0.049, respectively). We next examined by Western immunoblots the generation of 4-hydroxynoneal (HNE) and malondialdehyde (MDA), major products of lipid peroxidation, in the injured epicenter. There was a significant increase in 10 kDa HNE- and MDA-modified proteins in the HO-1+/- as compared with WT mice (P=0.037 and 0.043, respectively). Finally, we compared the degradation of myelin basic protein (MBP), an indicator of white matter damage, in the HO-1+/- and WT mice by Western immunoblots. There was significantly greater degradation of MBP in the HO-1+/- compared with WT mice (P=0.049). Together, these findings show that HO-1 modulates oxidative stress and white matter injury in the acutely injured spinal cord. This modulation may be partially attributed to the ability of HO-1 to stabilize the blood-spinal cord barrier and limit neutrophil infiltration.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aldehydes / pharmacology
  • Animals
  • Blood Vessels / enzymology
  • Blood Vessels / pathology
  • Blotting, Western
  • Brain / pathology*
  • Enzyme Induction / physiology
  • Heme Oxygenase (Decyclizing) / metabolism
  • Heme Oxygenase-1 / biosynthesis
  • Heme Oxygenase-1 / genetics
  • Heme Oxygenase-1 / physiology*
  • Immunohistochemistry
  • Inflammation / pathology
  • Male
  • Malondialdehyde / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myelin Basic Protein / metabolism
  • Neutrophil Infiltration / drug effects
  • Oxidative Stress / drug effects*
  • Spinal Cord / drug effects*
  • Spinal Cord / enzymology
  • Spinal Cord Injuries / pathology*

Substances

  • Aldehydes
  • Myelin Basic Protein
  • Malondialdehyde
  • Heme Oxygenase (Decyclizing)
  • Heme Oxygenase-1
  • 4-hydroxy-2-nonenal