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Research ArticleArticle

Effects of Pirfenidone on Procollagen Gene Expression at the Transcriptional Level in Bleomycin Hamster Model of Lung Fibrosis

S. N. Iyer, G. Gurujeyalakshmi and S. N. Giri
Journal of Pharmacology and Experimental Therapeutics April 1999, 289 (1) 211-218;
S. N. Iyer
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G. Gurujeyalakshmi
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S. N. Giri
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Abstract

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.

Footnotes

  • Send reprint requests to: Dr. Shri N. Giri, Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA 95616. E-mail: sngiri{at}ucdavis.edu

  • ↵1 This work was supported by National Heart, Lung, and Blood Institute Grant R01-HL56262.

  • Abbreviations:
    IPF
    interstitial pulmonary fibrosis
    i.t.
    intratracheal
    BL
    bleomycin
    PC
    procollagen
    PD
    pirfenidone
    SA
    saline
    CD
    control diet
    TGF-β
    transforming growth factor-β
    MDAE
    malondialdehyde equivalent
    ROS
    reactive oxygen species
    PH
    prolyl hydroxylase
    UV
    ultraviolet
    • Received March 25, 1998.
    • Accepted November 11, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 289 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 289, Issue 1
1 Apr 1999
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Research ArticleArticle

Effects of Pirfenidone on Procollagen Gene Expression at the Transcriptional Level in Bleomycin Hamster Model of Lung Fibrosis

S. N. Iyer, G. Gurujeyalakshmi and S. N. Giri
Journal of Pharmacology and Experimental Therapeutics April 1, 1999, 289 (1) 211-218;

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Research ArticleArticle

Effects of Pirfenidone on Procollagen Gene Expression at the Transcriptional Level in Bleomycin Hamster Model of Lung Fibrosis

S. N. Iyer, G. Gurujeyalakshmi and S. N. Giri
Journal of Pharmacology and Experimental Therapeutics April 1, 1999, 289 (1) 211-218;
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