Journal
FREE RADICAL BIOLOGY AND MEDICINE
Volume 34, Issue 1, Pages 124-133Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/S0891-5849(02)01295-9
Keywords
lung; knockout; pPeroxidase; NADPH cytochrome c P450 reductase; reactive iron; free radicals
Funding
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL058752, R29HL052701] Funding Source: NIH RePORTER
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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% 02) 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 H2O2. (C) 2002 Elsevier Science Inc.
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