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Vol. 289, Issue 1, 211-218, April 1999
Department of Molecular Biosciences, School of Veterinary Medicine,
University of California, Davis, California
A time course study was carried out to elucidate the mechanisms for
antifibrotic effect of pirfenidone (PD). Hamsters were intratracheally
(i.t.) instilled with saline (SA) or bleomycin (BL) (7.5 units/kg/5
ml). The animals were fed a diet containing 0.5% PD or the same
control diet (CD) without the drug 2 days before and throughout the
study. The animals were sacrificed at various times after instillation.
The lung hydroxyproline level in BL + CD groups was gradually increased
and peaked at 21 days to 181% of the SA + CD control. The BL + PD-treated groups showed a gradual decrease in their lung collagen
content, showing a maximum reduction of 40% at day 21. The lung
malondialdehyde levels of the BL + CD groups were increased by
several-fold of the corresponding SA + CD groups at various times. The
lung prolyl hydroxylase (PH) activities in the BL + CD groups were also
increased by several-fold of the corresponding SA + CD groups at these
time points. The hamsters in the BL + PD showed a gradual decrease in
the lung malondialdehyde levels from 10 to 21days compared with their
corresponding BL + CD groups. Treatment with PD also reduced the lung
PH activities in the BL + PD groups compared with the corresponding BL + CD groups. However, PD failed to manifest any direct inhibitory
effect on PH activity in vitro. BL treatment increased the lung
procollagen I and III gene expressions in the BL + CD groups by
several-fold at varying times compared with the corresponding SA + CD,
and treatment with PD in the BL + PD groups significantly
down-regulated the BL-induced overexpression of these genes. Studies
evaluating the regulation of these genes at the transcriptional level
revealed PD significantly reduced the transcription of PC I at 14 days. Our results indicate that the antifibrotic effect of PD was partly due
to suppression of the BL-induced inflammatory events and partly due to
down-regulation of BL-induced overexpression of lung procollagen I and
III genes.
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