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

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-R alpha and -R beta mRNA expression, and in PDGF-AA and -R alpha immunoreactivity, was demonstrated during the progressive loss of respiratory epithelium and airway occlusion in nontreated allografts compared with syngeneic grafts. Treatment with CCP 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%. CCP 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 -R alpha, 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.