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-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.
Kallio
E A
EA
Cardiopulmonary Research Group, Transplantation Laboratory, University of Helsinki, Finland. Erkki.Kallio@Helsinki.Fi
Koskinen
P K
PK
Aavik
E
E
Buchdunger
E
E
Lemström
K B
KB
D000818:Animals; D001989:Bronchiolitis Obliterans / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D002455:Cell Division / Q000187:drug effects; D002908:Chronic Disease; D016572:Cyclosporine / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006084:Graft Rejection / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008297:Male; D010982:Platelet-Derived Growth Factor / Q000502:physiology*; D016133:Polymerase Chain Reaction; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000378:metabolism; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism; D020545:Respiratory Mucosa / Q000473:pathology; D014132:Trachea / Q000378:metabolism / Q000473:pathology / Q000637:transplantation; D014184:Transplantation, Homologous; D014185:Transplantation, Isogeneic
C092972:CGP 53716; D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D010982:Platelet-Derived Growth Factor; D011725:Pyridines; D011743:Pyrimidines; D016572:Cyclosporine; D011505:Protein-Tyrosine Kinases; D020796:Receptor, Platelet-Derived Growth Factor alpha; D020797:Receptor, Platelet-Derived Growth Factor beta