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Published ahead of print on January 13, 2006, doi:10.1164/rccm.200505-717OC

Am. J. Respir. Crit. Care Med., Volume 173, Number 7, April 2006, 769-776

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Submitted on May 6, 2005
Accepted on January 9, 2006

Pharmacological Differentiation of Inflammation and Fibrosis in the Rat Bleomycin Model

Nveed I Chaudhary1, Andreas Schnapp1, and John E Park1*

1 Department of Pulmonary Research, Boehringer Ingelheim Pharma GmbH, Biberach an der Riss, Germany

* To whom correspondence should be addressed. 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. A number of 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 anti-inflammatory and anti-fibrotic treatments on efficacy. Methods and measurements: Rats were given single intra-tracheal (I.T.) injections of BLM on day 0. At specified timepoints, 10 rats were sacrificed and their lungs studied for pro-inflammatory cytokines and for pro- fibrotic growth factor mRNA. After a single I.T.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 days. Results: After BLM administration the expression of inflammatory cytokines was elevated and returned to background levels at later timepoints. Pro-fibrotic 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. Anti-inflammatory treatment (oral prednisolone) was beneficial when commenced at day 1, but had no effect if administered from day 10 onwards. However, Imatinib Mesylate was effective independently of the dosing regime. Conclusions: The response of the BLM model to anti-fibrotic or anti-inflammatory interventions is critically dependent on timing after the initial injury.
Key words: Bleomycin, Lung, Fibrosis, Imatinib Mesylate, Prednisolone




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