cgp-53716 and Chronic-Disease

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.

Topics: Animals; Bronchiolitis Obliterans; Cell Division; Chronic Disease; Cyclosporine; Enzyme Inhibitors; Graft Rejection; Immunohistochemistry; Immunosuppressive Agents; Male; Platelet-Derived Growth Factor; Polymerase Chain Reaction; Protein-Tyrosine Kinases; Pyridines; Pyrimidines; Rats; Rats, Inbred Strains; Receptor, Platelet-Derived Growth Factor alpha; Receptor, Platelet-Derived Growth Factor beta; Respiratory Mucosa; Trachea; Transplantation, Homologous; Transplantation, Isogeneic