Quantification of bleomycin pulmonary toxicity in mice by changes in lung hydroxyproline content and morphometric histopathology.
Bleomycin treatment produced dose-dependent changes in lung collagen content and in several measurable histopathological parameters. NIH/Swiss mice were treated twice weekly for 6 weeks with bleomycin, 0, 1, 20, or 40 mg/kg s.c. The two highest doses produced mortalities of 35 and 100%, respectively, as well as loss of body weight and increase in lung wet weight. Lung hydroxyproline content, an index of collagen, increased to 40 to 50% above control levels at 6 and 8 weeks after initiation of treatment with bleomycin 20 mg/kg. Morphometric analysis was applied to the following parameters at light microscopy: number of intraalveolar macrophages and leukocytes, total pulmonary cell count, alveolar wall thickness, and percentage of consolidation of lung parenchyma. The two highest doses produced increases in all of these parameters as compared to controls. The most marked changes occurred in the number of intraalveolar cells, which in the group given 20 mg/kg rose to 150, 190, and 210% of controls at 4, 6, and 8 weeks. The lowest dose of bleomycin, 1 mg/kg twice weekly for 6 weeks, evoked no pulmonary or other toxicity by the parameters examined. This model of chronic pulmonary toxicity may be useful in analog development, in testing potential antidotes, and in examining the effects of other factors that might modify the pulmonary toxicity of bleomycin.