Specific inhibitors of platelet-derived growth factor or epidermal growth factor receptor tyrosine kinase reduce pulmonary fibrosis in rats

Am J Pathol. 1999 Jul;155(1):213-21. doi: 10.1016/S0002-9440(10)65115-2.


The proliferation of myofibroblasts is a central feature of pulmonary fibrosis. In this study we have used tyrosine kinase inhibitors of the tyrphostin class to specifically block autophosphorylation of the platelet-derived growth factor receptor (PDGF-R) or epidermal growth factor receptor (EGF-R). AG1296 specifically inhibited autophosphorylation of PDGF-R and blocked PDGF-stimulated [3H]thymidine uptake by rat lung myofibroblasts in vitro. AG1478 was demonstrated as a selective blocker of EGF-R autophosphorylation and inhibited EGF-stimulated DNA synthesis in vitro. In a rat model of pulmonary fibrosis caused by intratracheal instillation of vanadium pentoxide (V2O5), intraperitoneal delivery of 50 mg/kg AG1296 or AG1478 in dimethylsulfoxide 1 hour before V2O5 instillation and again 2 days after instillation reduced the number of epithelial and mesenchymal cells incorporating bromodeoxyuridine (Brdu) by approximately 50% at 3 and 6 days after instillation. V2O5 instillation increased lung hydroxyproline fivefold 15 days after instillation, and AG1296 was more than 90% effective in preventing the increase in hydroxyproline, whereas AG1478 caused a 50% to 60% decrease in V2O5-stimulated hydroxyproline accumulation. These data provide evidence that PDGF and EGF receptor ligands are potent mitogens for collagen-producing mesenchymal cells during pulmonary fibrogenesis, and targeting tyrosine kinase receptors could offer a strategy for the treatment of fibrotic lung diseases.

MeSH terms

  • Animals
  • Collagen / antagonists & inhibitors
  • Collagen / metabolism
  • Enzyme Inhibitors / pharmacology*
  • ErbB Receptors / metabolism*
  • Lung / drug effects
  • Lung / metabolism
  • Lung / pathology
  • Mitosis / drug effects
  • Phosphorylation / drug effects
  • Pulmonary Fibrosis / metabolism
  • Pulmonary Fibrosis / pathology*
  • Quinazolines
  • Rats
  • Rats, Sprague-Dawley
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Receptors, Platelet-Derived Growth Factor / metabolism*
  • Tyrphostins / pharmacology


  • Enzyme Inhibitors
  • Quinazolines
  • Tyrphostins
  • 6,7-dimethoxy-3-phenylquinoxaline
  • RTKI cpd
  • Collagen
  • ErbB Receptors
  • Receptor Protein-Tyrosine Kinases
  • Receptors, Platelet-Derived Growth Factor