REDUCTION OF BLEOMYCIN-INDUCED ACUTE DNA INJURY IN THE RAT LUNG BY THE 21-AMINOSTEROID, U-74389G

Objective: To determine whether pretreatment with a 21-aminosteroid, U -74389G, can prevent subsequent DNA injury in bleomycin-exposed lungs. Subjects: Thirty-six adult male Sprague-Dawley rats. Design: Controll ed animal laboratory investigation of DNA injury in vivo. Intervention s: Animals were treated with 21-aminosteroid (10 mg/kg) or vehicle and subsequently received intratracheal instillation of bleomycin (1.75 U ) or normal saline. Measurements and Main Results: Twenty-four hours a fter bleomycin exposure, the 21-aminosteroid-treated animals had decre ased evidence of DNA injury, expressed as percentage of DNA fragmentat ion normalized to the control group (113.5 +/- 6 [SEM] VS. 132 +/- 3.9 %, p less than or equal to .05), and activity of the DNA repair enzyme poly ADP-ribose synthetase (3.4 +/- 0.2 vs. 5.6 +/- 0.9 pmol nicotina mide adenine dinucleotide/min/mg protein, p less than or equal to .05) . Only bleomycin-exposed (+ vehicle) animals demonstrated significant evidence of increased DNA injury vs. the intratracheal saline-exposed control groups. Conclusions: The 21-aminosteroid pretreatment decrease s subsequent pulmonary DNA injury induced by bleomycin exposure. This finding is likely due to the M-aminosteroid's iron-chelating and cell- permeating abilities, and suggests that these agents may be effective in other diseases where iron-dependent free radical reactions occur.