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Development of a bleomycin hamster model of subchronic lung fibrosis
1Department of Veterinary Pharmacology, School of Veterinary Medicine, University of California, Davis.
Abstract:
The existing bleomycin (BLM)-rodent model of lung fibrosis requires large doses and is often associated with morbidity and high mortality. We have developed an intratracheal multiple-dose BLM-hamster model of lung fibrosis. In this model, 3 consecutive doses of BLM (2.5 U, 2.0 U and 1.5 U/5mL/kg) were instilled intratracheally, one dose per week. The hamsters were killed at 10, 20, 30, 60 and 90 days after the last IT instillation and the lungs were lavaged or perfused with saline. This regimen of BLM administration was devoid of morbidity and caused only 6% overall mortality. Lung prolyl hydroxylase activity at 10 days and hydroxyproline content at 20, 30, 60 and 90 days were significantly higher than noted for the controls. Bronchoalveolar lavage fluid-supernatant protein and the total number of recovered cells of all types were significantly higher than observed for the controls at all times, except at 90 days. Lungs showed a multifocal mixed mononuclear infiltrate at 10 and 20 days and septal fibrosis, which was most severe and organized at 30 days and less severe at 60 and 90 days. The parenchymal lesions were significantly greater than those of the controls at all times, except at 10 days. This model, which required only 6 U BLM/kg, induced a moderate level of lung fibrosis. It has been concluded, therefore, that this model, inasmuch as it is not associated with an overwhelmingly acute inflammation, would be more applicable for screening potential antifibrotic agents than existing models of lung fibrosis.
Insights
A new bleomycin (BLM) hamster model for lung fibrosis uses lower doses with minimal mortality. This model effectively induces lung fibrosis and is suitable for screening antifibrotic drugs.
Area of Science:
- Pulmonary Medicine
- Toxicology
- Animal Models
Background:
- Existing bleomycin (BLM)-induced rodent models for lung fibrosis often require high doses, leading to significant morbidity and mortality.
- There is a need for more refined animal models to study lung fibrosis and screen antifibrotic agents effectively.
Purpose of the Study:
- To develop and characterize a novel intratracheal multiple-dose bleomycin (BLM)-hamster model for inducing lung fibrosis.
- To assess the safety, efficacy, and pathological outcomes of this new model compared to existing methods.
Main Methods:
- Hamsters received three weekly intratracheal instillations of BLM at decreasing doses (2.5 U, 2.0 U, and 1.5 U/kg).
- Lung tissues and bronchoalveolar lavage fluid were collected at various time points (10, 20, 30, 60, and 90 days) post-treatment.
- Histopathological analysis, prolyl hydroxylase activity, hydroxyproline content, and cellular counts were evaluated.
Main Results:
- The BLM-hamster model demonstrated low overall mortality (6%) and no significant morbidity.
- Elevated lung prolyl hydroxylase activity and hydroxyproline content confirmed fibrosis development.
- Increased protein and cell counts in bronchoalveolar lavage fluid indicated inflammation, resolving by 90 days.
- Histopathology revealed multifocal mononuclear infiltrates and progressive septal fibrosis.
Conclusions:
- The developed intratracheal multiple-dose BLM-hamster model successfully induces moderate lung fibrosis with reduced toxicity.
- This model's lower mortality and morbidity profile make it a valuable tool for screening potential antifibrotic agents.
- The model's characteristics suggest it is more applicable for antifibrotic drug screening than current rodent models.