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Mice Overexpressing Extracellular Superoxide Dismutase Are Resistant to Bleomycin-Induced Pulmonary Injury* FREE TO VIEW

Russell P. Bowler, MD; M. Nicks; J. D. Crapo, MD, FCCP
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*From the National Jewish Medical and Research Center, Denver, CO.

Correspondence to: Russell P. Bowler, MD, University of Colorado Health Sciences Center, National Jewish Research and Medical Center, 1400 Jackson St, Denver, CO 80206

Chest. 2001;120(1_suppl):S10. doi:10.1378/chest.120.1_suppl.S10
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Intratracheal bleomycin instillation is used to induce pulmonary inflammation and fibrosis in rodents. The free-radical superoxide is thought to play an important role in inducing this response. We hypothesized that extracellular superoxide dismutase (EC-SOD), the primary EC-SOD, will mitigate the inflammation and fibrosis from intratracheal bleomycin instillation. We also hypothesized that proteolytic cleavage of the heparin-binding carboxyterminus of EC-SOD increases during inflammation and fibrosis. Bleomycin, 4 U/kg, or saline solution was instilled into the trachea of C57/B6 mice that overexpress human EC-SOD using a lung-specific surfactant protein C promoter. Littermates that did not have the transgene were used as control mice. Animals were killed every week for 8 weeks. The right lung was homogenized and used for Western blotting with mouse- and human-specific EC-SOD antibodies. The left lung was embedded in paraffin and stained with hematoxylin-eosin to evaluate inflammation and fibrosis. There was a near-complete reduction in inflammation and fibrosis in the EC-SOD-overexpressing mice treated with bleomycin compared to the transgene-negative mice treated with bleomycin. This difference was most marked after 4 weeks. There were no significant differences in the ratio of cleaved to intact EC-SOD in treated vs untreated animals. Overexpression of human EC-SOD protein in the lung can protect against bleomycin-induced pulmonary inflammation and fibrosis. The mechanism of protection is likely due to a change in total EC-SOD content but does not correlate with proteolytic modifications of the enzyme SOD in the extracellular space. The mechanism of the polymer formation remains unknown.

Abbreviation: EC-SOD = extracellular superoxide dismutase

Supported by National Research Service Award 1 F32 HL 10220-01 and the Andrew Goodman Fellowship in Medicine.




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