Oxygen toxicity and iron accumulation in the lungs of mice lacking heme oxygenase-2

Phyllis A Dennery; Douglas R Spitz; Guang Yang; Arthur Tatarov; Christen S Lee; Mychelle L Shegog; Kenneth D Poss

doi:10.1172/JCI448

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Oxygen toxicity and iron accumulation in the lungs of mice lacking heme oxygenase-2

Journal article

Open access

Peer reviewed

Oxygen toxicity and iron accumulation in the lungs of mice lacking heme oxygenase-2

Phyllis A Dennery, Douglas R Spitz, Guang Yang, Arthur Tatarov, Christen S Lee, Mychelle L Shegog and Kenneth D Poss

The Journal of clinical investigation, Vol.101(5), pp.1001-1011

03/01/1998

DOI: 10.1172/JCI448

PMCID: PMC508651

PMID: 9486970

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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.

Gene Expression

Immunohistochemistry

Oxidative Stress

Animals

Antioxidants - analysis

Antioxidants - metabolism

Blotting, Western

Ferritins - analysis

Ferritins - metabolism

Glutathione - analysis

Glutathione - metabolism

Heme Oxygenase (Decyclizing) - analysis

Heme Oxygenase (Decyclizing) - genetics

Heme Oxygenase (Decyclizing) - immunology

Heme Oxygenase (Decyclizing) - metabolism

Hemeproteins - metabolism

Iron - analysis

Iron - metabolism

Lung - metabolism

Lung - pathology

Mice

Mice, Knockout

Oxidation-Reduction

Oxygen - toxicity

RNA, Messenger - metabolism

Transferrin - analysis

Transferrin - metabolism

Details

Title: Subtitle: Oxygen toxicity and iron accumulation in the lungs of mice lacking heme oxygenase-2
Creators: Phyllis A Dennery - Stanford University
Douglas R Spitz
Guang Yang
Arthur Tatarov
Christen S Lee
Mychelle L Shegog
Kenneth D Poss
Resource Type: Journal article
Publication Details: The Journal of clinical investigation, Vol.101(5), pp.1001-1011
DOI: 10.1172/JCI448
PMID: 9486970
PMCID: PMC508651
ISSN: 0021-9738
eISSN: 1558-8238
Grant note: HL-51469 / NHLBI NIH HHS HL-52701 / NHLBI NIH HHS
Language: English
Date published: 03/01/1998
Academic Unit: Pathology; Radiation Oncology; Fraternal Order of Eagles Diabetes Research Center
Record Identifier: 9984312980602771

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