DUAL ROLE OF VASCULAR ENDOTHELIAL GROWTH FACTOR IN EXPERIMENTAL OBLITERATIVE BRONCHIOLITIS

Abstract

P964 Aims: We investigated the role of vascular endothelial growth factor (VEGF) in the development of obliterative bronchiolitis (OB) in rat tracheal allografts. Methods: Tracheal allografts were transplanted heterotopically from DA- to WF-rats into the greater omentum. Syngeneic controls were performed DA to DA rats. Expression of VEGF ligand and receptor protein and mRNA was analysed from normal, syngeneic, and allogeneic tracheal transplants. Adenovirally mediated VEGF164 (AdVEGF) gene transfer was used to over-express VEGF while AdLacZ-treated allografts served as controls. PTK787, an inhibitor of VEGF receptor tyrosine kinase activity, was used for blocking VEGF action. Imatinib, an inhibitor of platelet-derived growth factor receptor (PDGFR) tyrosine kinase activity, was used to inhibit PDGF activity. Cyclosporine A (CyA) was used for background immunosuppression. Tracheal allografts were removed 10 and 30 days after transplantation for in situ hybridization, immunohistochemistry, and histology. Results: An increase in VEGF mRNA and protein expression was demonstrated in smooth muscle cells and mononuclear inflammatory cells of allograft airway wall compared to normal trachea and syngeneic grafts. Intragraft VEGF overexpression by adenoviral transfer of a mouse VEGF164 gene decreased early epithelial necrosis but increased microvascular remodeling and luminal occlusion by more than 50% compared to AdLacZ-treated control allografts. Inhibition of VEGF receptor tyrosine kinase activity with PTK787 negated the effect of VEGF overexpression. Although VEGFR inhibition with PTK787 increased early epithelial necrosis in uninfected allografts, it significantly reduced microvascular remodeling, intragraft infiltration by CD4+ and CD8+ T cells and the degree of luminal occlusion. Simultaneous adenoviral VEGF overexpression and treatment with a kinase inhibitor incorporating selectivity for PDGFR (imatinib) totally prevented luminal occlusion (Table 1). Table 1. Effect of the different treatment regimens on allograft histologyFigureConclusions: In conclusion, our findings indicate that VEGF has a dual role in transplant obliterative airway disease. VEGF may protect epithelial integrity by reducing the early ischemic injury. On the other hand, VEGF may increase luminal occlusion by enhancing inflammatory response and growth factor production. Thus, multiple treatment strategies may be needed to prevent transplant obliterative airway disease.