OXYGEN-TOXICITY AND IRON ACCUMULATION IN THE LUNGS OF MICE LACKING HEME OXYGENASE-2

Heme oxygenase (HO) activity leads to accumulation of the antioxidant bilirubin, and degradation of the prooxidant heme. Moderate overexpres sion of the inducible form, HO-1 is associated with protection against oxidative injury. However, the role of HO-2 in oxidative stress has n ot been explored, We evaluated survival, indices of oxidative injury, and lung and HO expression in HO-2 null mutant mice exposed to > 95% O -2 compared with wild-type controls, Similar basal levels of major lun g antioxidants were observed, except that the knockouts had a twofold increase in total glutathione content, Despite increased HO-1 expressi on from HO-1 induction, knockout animals were sensitized to hyperoxia- induced oxidative injury and mortality, and also had significantly inc reased markers of oxidative injury before hyperoxic exposure. Furtherm ore, during hyperoxia, lung hemoproteins and iron content were signifi cantly increased without increased ferritin, suggesting accumulation o f available redox-active iron. These results demonstrate that the abse nce of HO-2 is associated with induction of HO-1 and increased oxygen toxicity in vivo, apparently due to accumulation of lung iron. These r esults suggest that HO-2 functions to augment the turnover of lung iro n during oxidative stress, and that this function does not appear to b e compensated for by induction of HO-1 in the knockouts.