Published ahead of print on March 18, 2005, doi:10.1164/rccm.200408-1001OC Am. J. Respir. Crit. Care Med., Volume 171, Number 12, June 2005, 1421-1429 A more recent version of this article appeared on June 15, 2005
Submitted on August 3, 2004 Dual Role of Vascular Endothelial Growth Factor in Experimental Obliterative BronchiolitisRainer Krebs1,1 Cardiopulmonary Research Group, Transplantation Laboratory, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland, 2 Novartis Pharma, Basle, Switzerland, 3 Molecular Cancer Biology Laboratory, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland, 4 A.I. Virtanen Institute for Molecular Sciences, University of Kuopio, Kuopio, Finland, 5 Cardiopulmonary Research Group, Transplantation Laboratory, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland; Department of Medicine, Division of Nephrology, Helsinki University Central Hospital, Helsinki, Finland, 6 Cardiopulmonary Research Group, Transplantation Laboratory, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland; Department of Cardiothoracic Surgery, Helsinki University Central Hospital, Helsinki, Finland * To whom correspondence should be addressed. 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 to 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 to AdlacZ-treated allografts. Although VEGFR inhibition decreased early epithelial regeneration in non-infected 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 PDGFR 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 PDGF acting as a final effector molecule in this process. Key words: transplantation, lung, angiogenic growth factors
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