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Prevention of Lung Fibrosis in a Rabbit Model of Bleomycin-Induced Lung Fibrosis Upon Aerosol Application of Heparin or Urokinase* FREE TO VIEW

Andreas Günther, MD; Norbert Lübke, MD; Clemens Ruppert; Norbert Weissman, PhD; Friedrich Grimminger, MD, PhD; Werner Seeger, MD
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*From the Department of Internal Medicine, Justus-Liebig University Giessen, Giessen, Germany.

Correspondence to: Andreas Günther, MD, Zentrum für Innere Medizin, Medizinische Klinik II, Justus-Liebig-Universität Giessen, Klinikstrasse 36, 35392 Giessen, Germany

Chest. 2001;120(1_suppl):S4-S5. doi:10.1378/chest.120.1_suppl.S4
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Persistent alveolar fibrin formation may promote the development of lung fibrosis. To investigate this issue, pulmonary fibrosis was induced in New Zealand rabbits by aerosol application of 1.8 U/kg body weight bleomycin. As compared to saline solution-treated animals (n = 10), the bleomycin-exposed rabbits (n = 8) displayed a severe loss of compliance 28 days after challenge (approximately 1.8 mL/kg vs approximately 4 mL/kg body weight/mm Hg in control rabbits) and gas exchange was slightly impaired. Similarly, high-resolution CT, performed at end-inspiratory arrest under mechanical ventilation, showed a homogenously distributed reticular pattern, with a slight predominance in the basal lung regions. Aerosol application of heparin and urokinase during the early (days 2 to 12) and the late (days 14 to 24) phase was performed every second day by means of an ultrasonic device and under spontaneous breathing. We found that especially the early heparin (n = 7) treatment and late urokinase (n = 7) treatment, and to some extent also the early urokinase (n = 5) and late heparin (n = 7) treatment, significantly reduced the extent of the fibrotic changes on day 28. Lung compliance was measured at approximately 3 mL/kg (early heparin) and approximately 3.5 mL/kg (late urokinase) body weight/mm Hg, thus approximating that of control animals (approximately 4 mL/kg body weight/mm Hg). Accordingly, high-resolution CT scans revealed a clear reduction in the extent of fibrotic changes, with only a moderate extent of reticular changes. Gas exchange and ventilation pressure under mechanical ventilation of the isolated organs were similarly improved in these treatment groups. Soluble collagen content in BAL fluids and hydroxyproline content of homogenized tissue samples were markedly reduced in the treatment groups. We conclude that repetitive aerosol application of heparin or urokinase in the course of bleomycin-induced lung injury markedly reduces the extent of fibrotic changes seen at day 28 after bleomycin challenge.




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