Role of platelet-derived growth factor in obliterative bronchiolitis (chronic rejection) in the rat

Am J Respir Crit Care Med. 1999 Oct;160(4):1324-32. doi: 10.1164/ajrccm.160.4.9802006.


The role of platelet-derived growth factor (PDGF) in the development of obliterative bronchiolitis (OB) as a manifestation of chronic rejection was investigated in the heterotopic rat tracheal allograft model. An increase in intragraft PDGF-Ralpha and -Rbeta mRNA expression, and in PDGF-AA and -Ralpha immunoreactivity, was demonstrated during the progressive loss of respiratory epithelium and airway occlusion in nontreated allografts compared with syngeneic grafts. Treatment with CGP 53716, a protein-tyrosine kinase inhibitor selective for PDGF receptor, alone and in combination with suboptimal doses of cyclosporin A, significantly reduced myofibroproliferation and the degree of OB by more than 50%. CGP 53716 did not affect airway wall inflammatory cell proliferation, the number of graft-infiltrating CD4(+) or CD8(+) T cells, ED3(+) macrophages, or the level of immune activation determined as IL-2R and MHC class II expression. This study suggests a regulatory role for PDGF, especially for PDGF-AA and -Ralpha, in the development of obliterative bronchiolitis in this model, and demonstrates that inhibition of PDGF receptor protein-tyrosine kinase activation prevents these obliterative changes. Thus, receptor protein-tyrosine kinase inhibitors may provide a novel therapeutic strategy for the prevention of chronic rejection.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bronchiolitis Obliterans / metabolism
  • Bronchiolitis Obliterans / pathology
  • Bronchiolitis Obliterans / physiopathology*
  • Cell Division / drug effects
  • Chronic Disease
  • Cyclosporine / pharmacology
  • Enzyme Inhibitors / pharmacology
  • Graft Rejection / metabolism
  • Graft Rejection / pathology
  • Graft Rejection / physiopathology*
  • Immunohistochemistry
  • Immunosuppressive Agents / pharmacology
  • Male
  • Platelet-Derived Growth Factor / physiology*
  • Polymerase Chain Reaction
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Pyridines / pharmacology
  • Pyrimidines / pharmacology
  • Rats
  • Rats, Inbred Strains
  • Receptor, Platelet-Derived Growth Factor alpha / metabolism
  • Receptor, Platelet-Derived Growth Factor beta / metabolism
  • Respiratory Mucosa / pathology
  • Trachea / metabolism
  • Trachea / pathology
  • Trachea / transplantation
  • Transplantation, Homologous
  • Transplantation, Isogeneic


  • CGP 53716
  • Enzyme Inhibitors
  • Immunosuppressive Agents
  • Platelet-Derived Growth Factor
  • Pyridines
  • Pyrimidines
  • Cyclosporine
  • Protein-Tyrosine Kinases
  • Receptor, Platelet-Derived Growth Factor alpha
  • Receptor, Platelet-Derived Growth Factor beta