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: Controlled animal laboratory investigation of DNA injury in vivo. INTERVENTIONS: 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 after bleomycin exposure, the 21-aminosteroid-treated animals had decreased evidence of DNA injury, expressed as percentage of DNA fragmentation normalized to the control group (113.5 +/- 6 [SEM] vs. 132 +/- 3.9%, p < or = .05), and activity of the DNA repair enzyme poly ADP-ribose synthetase (3.4 +/- 0.2 vs. 5.6 +/- 0.9 pmol nicotinamide adenine dinucleotide/min/mg protein, p < or = .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 decreases subsequent pulmonary DNA injury induced by bleomycin exposure. This finding is likely due to the 21-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.