Role of platelet-derived growth factor and vascular endothelial growth factor in obliterative airway disease.
BACKGROUND
Platelet-derived growth factor (PDGF) is an important smooth muscle cell mitogen, and vascular endothelial growth factor (VEGF) is a known angiogenic and proinflammatory growth factor. We hypothesized that specific therapy aimed at these growth factors might inhibit the development of experimental obliterative airway disease (OAD).


METHODS
In fully mismatched rat tracheal allografts, we used imatinib and PTK/ZK, either alone or in combination, to block PDGF and VEGF receptor protein tyrosine kinase (RTK) action, respectively. Prophylaxis was initiated at the time of transplantation. Early treatment was commenced on Day 7 during the inflammatory phase and late treatment on Day 14 during the fibroproliferative phase of OAD. No immunosuppression was administered.


RESULTS
Prophylaxis with either PTK/ZK or imatinib alone significantly reduced OAD, and combined prophylaxis completely prevented its development. Early treatment with PTK/ZK and imatinib also effectively reduced the development of OAD. Late treatment failed to show significant efficacy. Blocking VEGF RTK action with PTK/ZK reduced the activation of allograft blood vessels and the number of lymph vessels in the allograft airway wall, and significantly diminished allograft inflammation, whereas PDGF blockade with imatinib inhibited the growth of smooth muscle cells in the proliferating lesion.


CONCLUSIONS
Combined prophylactic PDGF and VEGF RTK blockade completely prevents the development of OAD. Also, when early treatment with PTK/ZK and imatinib is commenced during the inflammatory phase of OAD development, it significantly attenuates the development of tracheal occlusion, suggesting that these drugs could potentially be used to treat bronchiolitis obliterans syndrome in its early phase.
Tikkanen
Jussi M
JM
Cardiopulmonary Research Group, Transplantation Laboratory, University of Helsinki and Helsinki University Central Hospital, PO Box 21 (Haartmaninkatu 3), FIN-00014 Helsinki, Finland. jussi.tikkanen@helsinki.fi
Hollmén
Maria
M
Nykänen
Antti I
AI
Wood
Jeanette
J
Koskinen
Petri K
PK
Lemström
Karl B
KB
D000818:Animals; D001549:Benzamides; D001989:Bronchiolitis Obliterans / Q000503:physiopathology*; D004359:Drug Therapy, Combination; D006023:Glycoproteins / Q000378:metabolism; D000068877:Imatinib Mesylate; D042601:Lymphatic Vessels / Q000378:metabolism; D008297:Male; D010793:Phthalazines / Q000627:therapeutic use; D010879:Piperazines / Q000627:therapeutic use; D010982:Platelet-Derived Growth Factor / Q000502:physiology*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011725:Pyridines / Q000627:therapeutic use; D011743:Pyrimidines / Q000627:therapeutic use; D051381:Rats; D011919:Rats, Inbred Strains; D017459:Receptors, Amino Acid / Q000502:physiology; D014132:Trachea / Q000473:pathology / Q000637:transplantation; D014184:Transplantation, Homologous; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
D001549:Benzamides; D006023:Glycoproteins; D010793:Phthalazines; D010879:Piperazines; D010982:Platelet-Derived Growth Factor; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011743:Pyrimidines; D017459:Receptors, Amino Acid; D042461:Vascular Endothelial Growth Factor A; C087659:tyrosine receptor; C404768:vatalanib; D000068877:Imatinib Mesylate; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2