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(Chest. 2001;120:S10.)
© 2001 American College of Chest Physicians

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

Russell P. Bowler, MD; M. Nicks and J. D. Crapo, MD, FCCP

* 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

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.

Footnotes

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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