Dasatinib attenuated bleomycin-induced pulmonary fibrosis in mice

Growth Factors. 2015;33(5-6):366-75. doi: 10.3109/08977194.2015.1109511. Epub 2015 Nov 25.

Abstract

Anti-fibrotic effect of dasatinib, a platelet-derived growth factor receptor (PDGFR) and Src-kinase inhibitor, was tested on pulmonary fibrosis (PF). Adult mice were divided into four groups: mice dissected 21 d after the bleomycin (BLM) instillation (0.08 mg/kg in 200 µl) (I) and their controls (II), and mice treated with dasatinib (8 mg/kg in 100 µl, gavage) for one week 14 d after BLM instillation and dissected 21 d after instillation (III) and their controls (IV). The fibrosis score and the levels of fibrotic markers were analyzed in lungs. BLM treatment-induced cell proliferation and increased the levels of collagen-1, alpha smooth muscle actin, phospho (p)-PDGFR-alpha, p-Src, p-extracellular signal-regulated kinases1/2 and p-cytoplasmic-Abelson-kinase (c-Abl) in lungs, and down-regulated PTEN expression. Dasatinib reversed these alterations in the fibrotic lung. Dasatinib limited myofibroblast activation and collagen-1 accumulation by the inhibition of PDGFR-alpha, and Src and c-Abl activations. In conclusion, dasatinib may be a novel tyrosine and Src-kinase inhibitor for PF regression in mice.

Keywords: ERK1/2; PDGFR-α; Pulmonary fibrosis; c-Abl; dasatinib; fibroblasts.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism
  • Animals
  • Antibiotics, Antineoplastic / adverse effects*
  • Antibiotics, Antineoplastic / pharmacology
  • Bleomycin / adverse effects*
  • Bleomycin / pharmacology
  • Cell Proliferation / drug effects
  • Collagen Type I / metabolism
  • Dasatinib / pharmacology*
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Lung / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • PTEN Phosphohydrolase / biosynthesis
  • Protein Kinase Inhibitors / pharmacology*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Pulmonary Fibrosis / chemically induced*
  • Pulmonary Fibrosis / prevention & control*
  • Receptor, Platelet-Derived Growth Factor alpha / metabolism
  • Receptors, Platelet-Derived Growth Factor / antagonists & inhibitors
  • src-Family Kinases / metabolism

Substances

  • Actins
  • Antibiotics, Antineoplastic
  • Collagen Type I
  • Protein Kinase Inhibitors
  • alpha-smooth muscle actin, mouse
  • Bleomycin
  • Receptor, Platelet-Derived Growth Factor alpha
  • Receptors, Platelet-Derived Growth Factor
  • src-Family Kinases
  • Proto-Oncogene Proteins c-akt
  • Extracellular Signal-Regulated MAP Kinases
  • PTEN Phosphohydrolase
  • Pten protein, mouse
  • Dasatinib