Effects of the 21-aminosteroid, U74389F, on bleomycin-induced pulmonary fibrosis in rats

Objective: To determine if a new class of agents, the 21-aminosteroids, which are reportedly potent inhibitors of iron-dependent lipid peroxidation, could protect rats from bleomycin-induced pulmonary fibrosis. Subjects: Fifty-five adult male Sprague-Dawley rats. Design: Prospective, randomized, blinded, controlled trial. Interventions: The rats were subjected to intratracheal bleomycin (or saline vehicle), and were then treated with the 21-aminosteroid, U74389F (20 mg/kg/day), or vehicle, for the next 7 days. Measurements and Main Results: At 21 days after bleomycin administration, pulmonary fibrosis was assessed histologically as percent of lung fields with evidence of fibrosis. Pulmonary fibrosis was assessed biochemically by measuring pulmonary elastin and hydroxyproline content. To determine if a protective effect of U74389F was linked to the 21-aminosteroid's ability to suppress lipid peroxidation, two products of lipid peroxidation were assayed in the lungs at 7 and 14 days after bleomycin exposure. By histologic assessment, the 21-aminosteroid-treated, bleomycin-exposed animals were found to have significantly decreased the extent of pulmonary fibrosis when compared with the bleomycin control group (mean 48.6 ± 20.0 [SD] % [n = 9] vs. 68.4 ± 19.6% [n = 11]; p < .05). In addition, lung elastin was decreased by ~75% (p < .05) and hydroxyproline was decreased by ~50% (NS) in the 21- aminosteroid-treated group when compared with the bleomycin control group. At 7 and 14 days after bleomycin exposure, all bleomycin-exposed animals had evidence of increased lipid peroxidation (conjugated dienes and thiobarbituric acid-reactive substances), but the 21-aminosteroid-treated, bleomycin-exposed animals had significantly decreased evidence of lipid peroxidation when compared with bleomycin controls. Conclusions: The 21- aminosteroid can substantially protect animals from bleomycin-induced pulmonary fibrosis and may prove useful in other lung diseases where iron- dependent, free-radical reactions and/or lipid peroxidation are presumed mechanisms of toxicity.