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Inhibition of Vascular Endothelial Growth Factor Receptors Causes Emphysema in Rats* FREE TO VIEW

Rubin M. Tuder, MD; Yasanori Kasahara, MD; Norbert F. Voelkel
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*From the University of Colorado Health Sciences Center, Denver, CO.

Correspondence to: Rubin M. Tuder, MD, University of Colorado Health Sciences Center, 4200 East 9th Ave, Denver, CO 80262

Chest. 2000;117(5_suppl_1):281S. doi:10.1378/chest.117.5_suppl_1.281S
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Abbreviations: KDR = kinase insert domain-containing receptor; VEGF = vascular endothelial growth factor

Vascular endothelial growth factor (VEGF) is perhaps the most important growth factor for endothelial cells. This growth factor is abundantly expressed in many different lung cells, including alveolar macrophages and type II cells. It acts through two different receptors that are mainly expressed on endothelial cells, kinase insert domain-containing receptor (KDR) and fetal liver tyrosine kinase. These receptor kinases affect intracellular calcium levels, and activation of KDR results in activation of the endothelial nitric oxide synthase and up-regulation of nitric oxide production. Since its discovery in cancers, the role of VEGF as an angiogenesis factor has been widely accepted. The abundance of VEGF expressed in normal lung tissue raises the question of a physiologic role for VEGF in the lung. We wondered whether VEGF not only is an endothelial cell growth factor, but perhaps also a survival factor for endothelial cells in the lung, particularly since VEGF-receptor blockade causes apoptosis in cultured endothelial cells. If indeed the signal transduction via VEGF and its receptor KDR is of principle importance for the maintenance of pulmonary endothelial cells, then chronic inhibition of VEGF receptors should lead to endothelial cell apoptosis and perhaps to emphysema.

The VEGF receptor kinase KDR inhibitor SU5416 was given via a subcutaneous injection to normal rats (three injections per week) over a 3-week period; some of the animals were exposed to chronic hypoxia, and others were kept at Denver altitude. After 3 weeks, the animals were killed following the measurement of pulmonary artery pressure and the lungs were examined histologically; the TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling) staining technique was applied in order to assess apoptotic events in the lung.

Chronic treatment of the animals with SU 516 for 3 weeks caused an increase in pulmonary artery pressure in both normoxic and hypoxic animals, widespread endothelial cell apoptosis, and emphysema when compared with drug vehicle-treated controls. The data suggest that VEGF/KDR signaling is required for the maintenance of alveolar structures, and we speculate that endothelial cell apoptosis contributes to emphysema function.




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