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

The proliferation of myofibroblasts is a central feature of pulmonary fibro sis. In this study we have used tyrosine kinase inhibitors of the tyrphosti n class to specifically block autophosphorylation of the platelet-derived g rowth factor receptor (PDGF-R) or epidermal growth factor receptor (EGF-R). AG1296 specifically inhibited autophosphorylation of PDGF-R and blocked PD GF-stimulated [H-3]thymidine uptake by rat lung myofibroblasts in vitro. AG 1478 was demonstrated as a selective blocker of EGF-R autophosphorylation a nd inhibited EGF-stimulated DNA synthesis in vitro. In a rat model of pulmo nary fibrosis caused by intratracheal instillation of vanadium pentoxide (V 2O5), intraperitoneal delivery of 50 mg/kg AG1296 or AG1478 in dimethylsulf oxide 1 hour before V2O5 instillation and again 2 days after instillation r educed the number of epithelial and mesenchymal cells incorporating bromode oxyuridine (Brdu) by similar to 50% at 3 and 6 days after instillation. V2O 5 instillation increased lung hydroxyproline fivefold 15 days after instill ation, and AG1296 was more than 90% effective in preventing the increase in hydroxyproline, whereas AG1478 caused a 50% to 60% decrease in V2O5-stimul ated hydroxyproline accumulation. These data provide evidence that PDGF and EGF receptor ligands are potent mitogens for collagen-producing mesenchyma l cells during pulmonary fibrogenesis, and targeting tyrosine kinase recept ors could offer a strategy for the treatment of fibrotic lung diseases.