Dual role of vascular endothelial growth factor in experimental obliterative bronchiolitis.
- PubMed: 17175244
Abstract
Obliterative bronchiolitis (OB) is the major limitation for long-term survival of lung allograft recipients. The exact molecular and cellular mechanisms contributing to obliterative lesion formation are unknown. Pathological characteristics of OB are epithelial damage, peribronchial inflammation, and increasing obliteration of bronchioli. Vascular endothelial growth factor (VEGF) is an angiogenic growth factor that exerts proinflammatory effects by increasing endothelial permeability and inducing expression of endothelial adhesion molecules. We investigated the role of VEGF in the development of OB in rat tracheal allografts and the role of VEGF receptors (VEGFR)-1 and -2 in the development of OB in mouse tracheal allografts. In nontreated allografts, with increasing loss of epithelium and airway occlusion, VEGF messenger RNA (mRNA) and protein expression vanished in the epithelium and increased in smooth muscle cells and mononuclear inflammatory cells compared with syngeneic grafts. Intragraft VEGF overexpression by adenoviral transfer of a mouse VEGF164 gene led to a decrease in epithelial necrosis but increased luminal occlusion by >50% compared with AdLacZ-treated rat tracheal allografts. When compared with the control immunoglobulin (Ig)G group, simultaneous treatment with antibodies against VEGFR-1 and -2 significantly lowered the degree of luminal occlusion of mouse tracheal allografts.
Author-supplied keywords
Dual role of vascular endothelial growth factor in experimental obliterative bronchiolitis.
Obliterative Bronchiolitis
Rainer Krebs1, Jussi M. Tikkanen1, Antti I. Nykänen1, Jeanette Wood2,
Michael Jeltsch3, Seppo Ylä-Herttuala4, Petri K. Koskinen1,5, Karl B. Lemström1,6
1Cardiopulmonary Research Group, Transplantation Laboratory, University of Helsinki and
Helsinki University Central Hospital, Helsinki, Finland;
2Novartis Pharma, Basle, Switzerland;
3Molecular Cancer Biology Laboratory, Biomedicum Helsinki, University of Helsinki, Helsinki,
Finland;
4A.I.Virtanen Institute for Molecular Sciences, University of Kuopio, Kuopio, Finland;
5Department of Medicine, Division of Nephrology, Helsinki University Central Hospital,
Helsinki, Finland;
6Department of Cardiothoracic Surgery, Helsinki University Central Hospital, Helsinki, Finland.
Address correspondence and requests for reprints to Karl Lemström, Transplantation Laboratory,
P.O.Box 21 (Haartmaninkatu 3), FIN-00014 Helsinki, Finland. Tel +358-9-19126590, Fax +358-
9-2411227, E-mail Karl.Lemstrom@Helsinki.Fi
This study was supported by grants from Helsinki University Central Hospital Research Funds,
the Sigrid Juselius Foundation, Finnish Life and Pension Insurance Companies, the Academy of
Finland (project no 1201292), Finska Läkaresällskapet, Jalmari and Rauha Ahokas Foundation,
and the Research and Science Foundation of Farmos.
This article has an online data supplement, which is accessible from this issue's table of content
online at www.atsjournals.org
Short running head: VEGF in obliterative bronchiolitis
Descriptor number: 162, Word count: 3657
AJRCCM Articles in Press. Published on March 18, 2005 as doi:10.1164/rccm.200408-1001OC
Copyright (C) 2005 by the American Thoracic Society.
Abstract
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 non-
immunosuppressed 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.
Word count: 199
Key words: transplantation, lung, angiogenic growth factors
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