Cysteinyl-leukotriene 1 receptor antagonist attenuates bleomycin-induced pulmonary fibrosis in mice

Life Sci. 2007 Apr 24;80(20):1882-6. doi: 10.1016/j.lfs.2007.02.038. Epub 2007 Mar 12.

Abstract

Leukotrienes are lipid mediators of inflammation derived from the 5-lipoxygenase pathway of arachidonic acid metabolism, and recent evidence suggests that they play an important role in pulmonary fibrosis. Montelukast is a cysteinyl-leukotriene 1 receptor antagonist that has been found to reduce airway remodeling, including subepithelial fibrosis, in a murine model of asthma, but the therapeutic effect of montelukast on pulmonary fibrosis remains unclear. In this study, we investigated whether montelukast is capable of preventing bleomycin-induced pulmonary fibrosis in mice. On day 1, C57BL/6 mice were given a single intratracheal injection of bleomycin (2.5 mg/kg), and montelukast (1.0 mg/kg) or vehicle alone subcutaneously 2 h later and on days 1-5 of each week for two weeks. The total number of cells in bronchoalveolar lavage fluid (BALF) was reduced in the montelukast group on day 7 and on day 14, and cellular inflammation and fibrosis were attenuated on day 14 as indicated by significant decrease in the Ashcroft score and lung hydroxyproline content. Although cysteinyl-leukotriene level in BALF was not significantly different, transforming growth factor beta (TGFbeta) level in BALF by ELISA and TGFbeta expression in lung tissue by immunohistochemistry was reduced on day 14 in the montelukast group. The results of this study show that montelukast inhibits the inflammatory process and development of bleomycin-induced pulmonary fibrosis in mice and that these effects may be associated with a decrease in TGFbeta expression. They also suggest that montelukast may serve as a new therapy for patients with interstitial pulmonary fibrosis.

MeSH terms

  • Animals
  • Bleomycin
  • Bronchoalveolar Lavage Fluid / cytology*
  • Cysteine / metabolism*
  • Disease Models, Animal
  • Hydroxyproline / metabolism*
  • Leukotriene Antagonists / therapeutic use*
  • Leukotrienes / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Pulmonary Fibrosis / chemically induced
  • Pulmonary Fibrosis / prevention & control*
  • Receptors, Leukotriene / metabolism
  • Transforming Growth Factor beta / metabolism

Substances

  • Leukotriene Antagonists
  • Leukotrienes
  • Receptors, Leukotriene
  • Transforming Growth Factor beta
  • cysteinyl-leukotriene
  • Bleomycin
  • Cysteine
  • Hydroxyproline