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Pharmacologic Differentiation of Inflammation and Fibrosis in the Rat Bleomycin Model

Department of Pulmonary Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany

Correspondence and requests for reprints should be addressed to Dr. John Park, Ph.D., Department of Pulmonary Research, Boehringer Ingelheim Pharma GmbH & Co., KG Birkendorferstrae 65, Biberach an der Riss D-88937, Germany. E-mail: john.park{at}bc.boehringer-ingelheim.com

Rationale: The model most often used to study the pathogenesis of pulmonary fibroses is the bleomycin (BLM)-induced lung fibrosis model. Several treatments have been efficacious in this model, but not in the clinic.

Objectives: To describe the time course of inflammation and fibrosis in the BLM model and to study the effect of timing of antiinflammatory and antifibrotic treatments on efficacy.

Methods and Measurements: Rats were given single intratracheal injections of BLM on Day 0. At specified time points, 10 rats were killed and their lungs studied for proinflammatory cytokines and for profibrotic growth factor mRNA. After a single intratracheal injection of BLM on Day 0, rats were treated from Day 1 or 10 daily with oral prednisolone (10 mg/kg) or oral imatinib mesylate (50 mg/kg) for 21 d.

Results: After BLM administration, the expression of inflammatory cytokines was elevated and returned to background levels at later time points. Profibrotic gene expression peaked between Days 9 and 14 and remained elevated till the end of the experiment, suggesting a "switch" between inflammation and fibrosis in this interval. Antiinflammatory treatment (oral prednisolone) was beneficial when commenced at Day 1, but had no effect if administered from Day 10 onward. However, imatinib mesylate was effective independently of the dosing regime.

Conclusions: The response of the BLM model to antifibrotic or antiinflammatory interventions is critically dependent on timing after the initial injury.

Key Words: bleomycin • fibrosis • imatinib mesylate • lung • prednisolone

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