ABSTRACT
Heme oxygenase (HO) activity leads to accumulation of the antioxidant bilirubin, and degradation of the prooxidant heme. Moderate overexpression of the inducible form, HO-1, is associated with protection against oxidative injury. However, the role of HO-2 in oxidative stress has not been explored. We evaluated survival, indices of oxidative injury, and lung and HO expression in HO-2 null mutant mice exposed to > 95% O2 compared with wild-type controls. Similar basal levels of major lung antioxidants were observed, except that the knockouts had a twofold increase in total glutathione content. Despite increased HO-1 expression from HO-1 induction, knockout animals were sensitized to hyperoxia-induced oxidative injury and mortality, and also had significantly increased markers of oxidative injury before hyperoxic exposure. Furthermore, during hyperoxia, lung hemoproteins and iron content were significantly increased without increased ferritin, suggesting accumulation of available redox-active iron. These results demonstrate that the absence of HO-2 is associated with induction of HO-1 and increased oxygen toxicity in vivo, apparently due to accumulation of lung iron. These results suggest that HO-2 functions to augment the turnover of lung iron during oxidative stress, and that this function does not appear to be compensated for by induction of HO-1 in the knockouts.
Subject(s)
Heme Oxygenase (Decyclizing)/metabolism , Iron/metabolism , Lung/metabolism , Lung/pathology , Oxygen/toxicity , Animals , Antioxidants/analysis , Antioxidants/metabolism , Blotting, Western , Ferritins/analysis , Ferritins/metabolism , Gene Expression , Glutathione/analysis , Glutathione/metabolism , Heme Oxygenase (Decyclizing)/analysis , Heme Oxygenase (Decyclizing)/genetics , Heme Oxygenase (Decyclizing)/immunology , Hemeproteins/metabolism , Immunohistochemistry , Iron/analysis , Mice , Mice, Knockout , Oxidation-Reduction , Oxidative Stress , RNA, Messenger/metabolism , Transferrin/analysis , Transferrin/metabolismABSTRACT
Detection and characterization of distinct central nervous system (CNS) tumor cell types is clinically important since distinct tumor types are associated with different prognoses and treatments. However, there is currently a lack of markers to identify certain glioma types and insufficient understanding as to which cells give rise to different glioma cell types. In the present study, biopsy specimens from human brain tumors were analyzed for expression of Myelin Transcription Factor 1 (MYT1) to explore the extent to which glioma cells reflect characteristic expression of MYT1 in developing glial progenitor cells. Immunostaining with an antibody against MYT1 revealed widespread immunoreactivity that was most prominent in high-grade oligodendrogliomas, astrocytomas, and mixed oligoastrocytomas as well as in a dysembryoplastic neuroepithelial tumor. MYT1 immunoreactivity in tumor regions generally correlated with the prevalence of cells exhibiting nuclear immunolabeling with an antibody against Ki-67, suggesting an association of MYT1 with cell proliferation that was also observed in normal adult human and rat brain in the germinal subependymal zone. The MYT1 immunoreactivity was frequently nuclear, appearing as dotted or punctate, but in some cases it was localized to the cytoplasm. In combination with histopathological studies and analysis of Ki-67 immunoreactivity, examination of MYT1 immunolabeling may provide additional information to aid in the detection and diagnosis of CNS tumors.
