Heme oxygenase-1 stabilizes the blood-spinal cord barrier and limits oxidative stress and white matter damage in the acutely injured murine spinal cord.
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.
Lin
Yong
Y
Department of Neurological Surgery, University of California at San Francisco, San Francisco, California 94143-0520, USA.
Vreman
Hendrik J
HJ
Wong
Ronald J
RJ
Tjoa
Tjoson
T
Yamauchi
Toshihiro
T
Noble-Haeusslein
Linda J
LJ
D000447:Aldehydes / Q000494:pharmacology; D000818:Animals; D001808:Blood Vessels / Q000201:enzymology / Q000473:pathology; D015153:Blotting, Western; D001921:Brain / Q000473:pathology*; D004790:Enzyme Induction / Q000502:physiology; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D007150:Immunohistochemistry; D007249:Inflammation / Q000473:pathology; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D004676:Myelin Basic Protein / Q000378:metabolism; D020556:Neutrophil Infiltration / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects*; D013116:Spinal Cord / Q000187:drug effects* / Q000201:enzymology; D013119:Spinal Cord Injuries / Q000473:pathology*
D000447:Aldehydes; D004676:Myelin Basic Protein; D008315:Malondialdehyde; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C027576:4-hydroxy-2-nonenal