Adult respiratory distress syndrome (ARDS) affects 150,000 individuals in the US annually with a mortality of 40 percent. Current treatment is supportive only. New therapies will require a detailed understanding of the molecular basis for this disorder. One of the earliest manifestations of ARDS is the development of noncardiogenic pulmonary edema. We have made the novel observation that pulmonary edema is induced by overexpression of the vascular endothelial growth factor (VEGF) gene in lung using a modified adenovirus vector approach. Gene transfer and overexpression of VEGF were confirmed by Northern analysis of mouse lung extracts and ELISA. Edema was observed in lung histology and quantified by lung wet-to-dry weight ratio and pulmonary capillary permeability to macromolecules by the Evan's blue dye assay and 131 l-albumin lung leak. This proposal will fully characterize the mechanism of VEGF-induced pulmonary edema with regard to endothelial permeability, alveolar dysfunction, VEGF receptor(s) specificity, signal transduction pathways and downstream effectors that mediate the edema. Ultrastructual information will be obtained by electron microscopy of VEGF-overexpressing lungs. Structure-function relationships of VEGF isoforms to the development of pulmonary edema will be defined using Ad vectors containing the genes for the various VEGF isoforms as well as mutant VEGFs which have specificity for binding to a particular VEGF receptor. Overexpression, immunoinhibition and pharmacologic inhibitor studies will define the roles of potential mediators downstream from VEGF such as endothelial nitric oxide synthase and nitric oxide and the intracellular signaling pathways that are activated during VEGF-induced edema. Studies to assess the potential role of activated neutrophils as a source of VEGF in vivo during acute lung injury will be developed. Bronchoalveolar lavage and plasma levels of VEGF will be measured in patients with acute lung injury to develop the hypothesis that overexpression of VEGF in lung may be one mechanism favoring increased permeability.
| Ware, L B; Kaner, R J; Crystal, R G et al. (2005) VEGF levels in the alveolar compartment do not distinguish between ARDS and hydrostatic pulmonary oedema. Eur Respir J 26:101-5 |
| Amano, Hideki; Hackett, Neil R; Kaner, Robert J et al. (2005) Alteration of splicing signals in a genomic/cDNA hybrid VEGF gene to modify the ratio of expressed VEGF isoforms enhances safety of angiogenic gene therapy. Mol Ther 12:716-24 |
| Kaner, Robert J; Crystal, Ronald G (2004) Pathogenesis of high altitude pulmonary edema: does alveolar epithelial lining fluid vascular endothelial growth factor exacerbate capillary leak? High Alt Med Biol 5:399-409 |
