Effect of nilotinib on bleomycin-induced acute lung injury and pulmonary fibrosis in mice

Respiration. 2011;82(3):273-87. doi: 10.1159/000327719. Epub 2011 Jun 9.

Abstract

Background: The tyrosine kinase inhibitor imatinib mesylate was developed as an inhibitor of the kinase activity of BCR-ABL. However, imatinib also has potent inhibitory activity against the platelet-derived growth factor receptor (PDGFR). Nilotinib is approved for treating patients with chronic myeloid leukemia showing resistance or intolerance to imatinib. Like imatinib, nilotinib selectively inhibits the tyrosine kinase activity of PDGFR.

Objectives: We examined the effect of imatinib and nilotinib on acute lung injury and pulmonary fibrosis in a mouse model.

Methods: Mice were treated by intratracheal instillation of bleomycin. Imatinib or nilotinib were administered by oral gavage. To study the early inflammatory and late fibrotic phases of lung injury, mice were sacrificed on days 3, 7, 14 and 21 after bleomycin instillation.

Results: Histopathology showed that imatinib and nilotinib attenuated the extent of lung injury and fibrosis. The numbers of inflammatory cells and levels of IL-6, IL-1β and tumor necrosis factor-α were decreased in the imatinib and nilotinib groups on days 3 and 7. Imatinib and nilotinib therapy significantly reduced the levels of hydroxyproline on days 14 and 21, which was accompanied by decreased expression levels of transforming growth factor (TGF)-β1 and PDGFR-β. Imatinib and nilotinib also significantly reduced the expression levels of the genes for TGF-β1 and platelet-derived growth factor (PDGF). Imatinib and nilotinib treatment also significantly inhibited the PDGF-induced proliferation of lung fibroblasts in vitro. When imatinib or nilotinib was given 7 days after the instillation of bleomycin, only nilotinib attenuated pulmonary fibrosis.

Conclusions: Imatinib and nilotinib attenuated bleomycin-induced acute lung injury and pulmonary fibrosis in mice. In a therapeutic model, nilotinib showed more potent antifibrotic effects than imatinib.

MeSH terms

  • Acute Lung Injury / chemically induced
  • Acute Lung Injury / drug therapy*
  • Acute Lung Injury / physiopathology
  • Animals
  • Antibiotics, Antineoplastic / adverse effects
  • Benzamides
  • Biomarkers, Tumor / metabolism
  • Bleomycin / adverse effects*
  • Blotting, Western
  • Gene Expression Regulation
  • Imatinib Mesylate
  • Interleukin-1beta / metabolism
  • Interleukin-6 / metabolism
  • Male
  • Mice
  • Piperazines / pharmacology
  • Protein Kinase Inhibitors / pharmacology*
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Pulmonary Fibrosis / chemically induced
  • Pulmonary Fibrosis / drug therapy*
  • Pulmonary Fibrosis / physiopathology
  • Pyrimidines / pharmacology*
  • Real-Time Polymerase Chain Reaction
  • Time Factors
  • Transforming Growth Factor beta1 / metabolism
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • 4-methyl-N-(3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((4-pyridin-3-ylpyrimidin-2-yl)amino)benzamide
  • Antibiotics, Antineoplastic
  • Benzamides
  • Biomarkers, Tumor
  • Interleukin-1beta
  • Interleukin-6
  • Piperazines
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Transforming Growth Factor beta1
  • Tumor Necrosis Factor-alpha
  • Bleomycin
  • Imatinib Mesylate
  • Protein-Tyrosine Kinases