High dose continuous infusion of bleomycin in mice: a new model for drug-induced pulmonary fibrosis

Abstract

Bleomycin (BLM) produces pulmonary fibrosis in mice when given as a single intratracheal injection, a single i.v. injection or multiple s.c. injections. All of these models are associated with significant disadvantages including a variable distribution of lesions, high mortality or a requirement for multiple procedures. We have developed a convenient method of BLM treatment that avoids these difficulties and yields extensive, reproducible pulmonary fibrosis in mice. Osmotic minipumps containing BLM (100 mg/kg) were implanted s.c. in C57Bl/6 mice and the drug was delivered as a continuous s.c. infusion over 1 week. No mortality occurred over the first 5 weeks after pump placement whereas i.v. BLM (80 mg/kg) produced 50% mortality within 2 weeks. BLM given by pump infusion produced a greater increase (P less than .05) in lung hydroxyproline after 6 weeks (70%) than a similar total dose given as multiple s.c. injections (40%). Lungs from pump-treated mice showed confluent subpleural fibrosis involving almost 50% of the pleural surface and evidence of subpleural alveolar collapse. Mice receiving i.v. or s.c. injections showed involvement of only 10 to 15% of the pleural surface. BALB/c mice were resistant to pulmonary fibrosis after pump implantation, indicating a murine strain difference in pulmonary responsiveness to BLM administered by constant infusion. This superior model for drug-induced pulmonary fibrosis uses a single procedure and provides an extensive, reproducible lung lesion. Additionally, our studies suggest that dysfunction of the pulmonary epithelium may play an important role in progressive pulmonary disease after BLM treatment.