Am. J. Respir. Crit. Care Med., Volume 160, Number 4, October 1999, 1324-1332

Role of Platelet-derived Growth Factor in Obliterative Bronchiolitis (Chronic Rejection) in the Rat

ERKKI A. KALLIO, PETRI K. KOSKINEN, EINARI AAVIK, ELISABETH BUCHDUNGER, and KARL B. LEMSTRÖM

Cardiopulmonary Research Group, Transplantation Laboratory, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland; and Novartis, Basel, Switzerland

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 and -R mRNA expression, and in PDGF-AA and -R 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 -R, 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.

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