Resistance to hyperoxia with heme oxygenase-1 disruption: role of iron.
In many models, a protective role for heme oxygenase-1 (HO-1), the rate-limiting enzyme in heme degradation, has been demonstrated. Also, HO-1 null mice (KO) are more susceptible to inflammation and hypoxia and transplant rejection. Nonetheless, their response to hyperoxia (> 95% O(2)) has not yet been evaluated. Surprisingly, after acute hyperoxic exposure, KO had significantly decreased markers of lung oxidative injury and survived chronic hyperoxia as well as wild-type (WT) controls. Disrupted HO-1 expression was associated with decreased lung reactive iron and iron-associated proteins, decreased NADPH cytochrome cp450 reductase activity, and decreased lung peroxidase activity compared to WT. Injection of tin protoporphyrin, an inhibitor of HO, in the WT decreased acute hyperoxic lung injury, whereas transduction of human HO-1 in the KO reversed the relative protection of the KO to acute injury and worsened hyperoxic survival. This suggests that disruption of HO-1 protects against hyperoxia by diminishing the generation of toxic reactive intermediates in the lung via iron and H(2)O(2).
Dennery
Phyllis A
PA
Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94304, USA. dennery@stanford.edu
Visner
Gary
G
Weng
Y i-Hao
Yi
Nguyen
Xuandai
X
Lu
Fuhua
F
Zander
Dani
D
Yang
Guang
G
D000818:Animals; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics / Q000378:metabolism*; D018496:Hyperoxia / Q000378:metabolism*; D007501:Iron / Q000378:metabolism*; D008168:Lung / Q000201:enzymology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013379:Substrate Specificity
D007501:Iron; D006419:Heme Oxygenase (Decyclizing)