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Dual Role of Vascular Endothelial Growth Factor in Experimental Obliterative Bronchiolitis

Cardiopulmonary Research Group, Transplantation Laboratory, University of Helsinki/Helsinki University Central Hospital; Molecular Cancer Biology Laboratory, Biomedicum Helsinki, University of Helsinki; Division of Nephrology, Department of Medicine, and Department of Cardiothoracic Surgery, Helsinki University Central Hospital, Helsinki; A.I. Virtanen Institute for Molecular Sciences, University of Kuopio, Kuopio, Finland; and Novartis Pharma, Basel, Switzerland

Correspondence and requests for reprints should be addressed to Karl Lemström, M.D., Ph.D., Transplantation Laboratory, P.O. Box 21 (Haartmaninkatu 3), FIN-00014 Helsinki, Finland. E-mail: karl.lemstrom{at}helsinki.fi

Obliterative bronchiolitis (OB) is the major limitation for long-term survival of lung allograft recipients. We investigated the role of vascular endothelial growth factor (VEGF) in the development of OB in rat tracheal allografts. In nonimmunosuppressed allografts, VEGF mRNA and protein expression vanished in the epithelium and increased in smooth muscle cells and mononuclear inflammatory cells with progressive loss of epithelium and airway occlusion compared with syngeneic grafts. Intragraft VEGF overexpression by adenoviral transfer of a mouse VEGF₁₆₄ gene increased early epithelial cell proliferation and regeneration but increased microvascular remodeling and lymphangiogenesis and luminal occlusion by more than 50% compared with AdlacZ-treated allografts. Although VEGF receptor inhibition decreased early epithelial regeneration in noninfected allografts, it reduced microvascular remodeling, lymphangiogenesis, intragraft traffic of CD4⁺ and CD8⁺ T cells, and the degree of luminal occlusion. Simultaneous VEGF gene transfer and platelet-derived growth factor receptor inhibition with imatinib preserved respiratory epithelium and totally prevented luminal occlusion. In conclusion, our findings indicate that VEGF has a dual role in transplant OB. Our results suggest that VEGF may protect epithelial integrity. On the other hand, VEGF may enhance luminal occlusion by increasing the recruitment of mononuclear inflammatory cells with platelet-derived growth factor acting as a final effector molecule in this process.

Key Words: angiogenic growth factors • lung • transplantation

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