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
A more recent version of this article appeared on April 1, 2006
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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