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Role of Platelet-derived Growth Factor and Vascular Endothelial Growth Factor in Obliterative Airway Disease

Cardiopulmonary Research Group, Transplantation Laboratory, University of Helsinki/Helsinki University Central Hospital; Division of Nephrology, Department of Medicine, and Department of Cardiothoracic Surgery, Helsinki University Central Hospital, Helsinki, Finland; and Novartis, Basel, Switzerland

Correspondence and requests for reprints should be addressed to Jussi Tikkanen, M.D., Ph.D., Cardiopulmonary Research Group, Transplantation Laboratory, University of Helsinki and Helsinki University Central Hospital, P.O. Box 21 (Haartmaninkatu 3), FIN-00014 Helsinki, Finland. E-mail: jussi.tikkanen{at}helsinki.fi

Rationale: 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.

Measurements and Main 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.

Key Words: lung transplantation • obliterative bronchiolitis • chronic rejection • angiogenic growth factors

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Recent observations have linked platelet-derived growth factor and vascular endothelial growth factor to the development of obliterative bronchiolitis. Novel receptor tyrosine kinase inhibitors targeting these growth factors may inhibit the progression of obliterative bronchiolitis. What This Study Adds to the Field Selective inhibition of platelet-derived growth factor and vascular endothelial growth factor receptor activity with clinically relevant tyrosine kinase inhibitors effectively prevents the development and progression of obliterative airway disease. Combined inhibition of both growth factors completely prevents airway obliteration.

 

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