) Emphysema is caused by a loss of alveolar lung structures. For the purpose of this application, the investigators focus on one important aspect of inflammation: oxidant stress. The investigators believe that the oxidant stress, such as induced by inflammation in chronic obstructive pulmonary diseases, compromises the endothelial and epithelial molecular programs that ultimately maintain the structural and cellular integrity of the adult human lung. The investigators hypothesize that the disappearance of lung alveoli in centrilobular emphysema occurs by apoptosis of capillary endothelial cells due to decreased expression of lung Vascular Endothelial Growth Factor (VEGF) and its receptor KDR. The investigators also propose that oxidant stress (oxidants, reactive oxygen or nitrogen species), that may be induced by lung inflammation, or in lung resident cells, causes lung endothelial cell death after interruption of VEGF/KDR survival signaling. The investigators' experimental approach relies on inhibition of KDR by the specific inhibitor SU5416 (from SUGEN Corp.).
The specific aims of this proposal are: 1) to determine whether chronic blockade of the VEGF-receptor KDR with SU5416 causes emphysema in rats. The investigators will also investigate whether SU5416- induced emphysema involves endothelial cell death, lung inflammation, and oxidant stress. The investigators will also address whether caspase inhibition prevents emphysema induced by SU5416; 2) to determine whether oxidant stress causes endothelial cell death and emphysema. The investigators will also determine whether oxidant stress decreases VEGF gene expression or modified KDR posttranslationally and whether it enhances the effect of SU5416 in rat lung; and 3) to determine whether scavenging lung oxidants with a SOD mimetic prevents the development of emphysema caused by KDR blockade or lung oxidant stress. The investigators' approach is to investigate rat models of emphysema caused by KDR receptor blockade or oxidant stress, to quantify the extent of emphysema using the mean linear intercept and functionally characterize the lung using pressure/volume curves, to assess lung alveolar septal endothelial cell death and lung caspase activity, to assay the lung tissue for several markers of oxidant stress (nitrotyrosine, products of lipid peroxidation, isoprostanes, carbonyl proteins). In cultured endothelial cells, the investigators will investigate in depth whether oxidant stress causes nitrosylation of the KDR receptor and thus alters KDR signaling. The investigators believe that the in depth exploration of these models will render results that are highly relevant to the human condition. The experimental results may point the way towards a new treatment/prevention strategy, i.e., inhibition of lung alveolar septal endothelial cell apoptosis and oxidant stress.
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