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Cigarette Smoke Extract Decreases the Expression of Vascular Endothelial Growth Factor by Cultured Cells and Triggers Apoptosis of Pulmonary Endothelial Cells* FREE TO VIEW

R. M. Tuder, MD; K. Wood; L. Taraseviciene; S. C. Flores, PhD; N. F. Voekel, MD
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*From the Departments of Pathology and Medicine, Division of Respiratory Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Denver, CO.

Correspondence to: Rubin M. Tuder, MD, Division of Pulmonary Science and Critical Care Medicine, University of Colorado Health Sciences Center, 4200 East 9th Ave, Denver, CO 80262

Chest. 2000;117(5_suppl_1):241S-242S. doi:10.1378/chest.117.5_suppl_1.241S
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Abbreviations: CSE = cigarette smoke extract; VEGF = vascular endothelial cell growth factor.

The mechanisms behind the disappearance of lung tissue (“vanishing lung”) in COPD remain enigmatic in spite of the commonly discussed hypotheses of lung inflammation and a protease-antiprotease imbalance. We postulate that there are cellular and molecular programs that maintain the structure of the adult lung. One or several of such lung cell maintenance programs, in particular for lung endothelial cells, is disrupted by the toxic effect of chronic cigarette smoke in genetically susceptible patients, thus resulting in centrilobular emphysema. Specifically, we hypothesize that disappearance of lung alveoli resulting in centrilobular emphysema occurs by apoptosis after decreased expression or activity of lung vascular endothelial cell growth factor (VEGF) or its receptors due to smoking. In the present work, we focused on the effect of cigarette smoke extract (CSE) on VEGF gene expression, on endothelial cell apoptosis, and on the ratio of the transcription factors Sp1 and Sp3, which are involved in the regulation of VEGF receptor kinase domain receptor expression in endothelial cells.

CSE treatment (10% for 24 h) of the monocytic U937, the hepatocellular carcinoma HepG2, and the lung carcinoma A549 cell lines decreases VEGF protein and messenger RNA expression as assessed by Western blot and ribonuclease protection assay. CSE also increased approximately twofold the production of nitric oxide by all cell lines tested. CSE (10% for 24 h) resulted in apoptosis and complete detachment from the culture dish of bovine pulmonary artery endothelial cells, while minimal detachment and apoptosis were seen with the U937, HepG2, and A549 cells. CSE treatment (1 and 0.1% for 6 h) of bovine pulmonary artery endothelial cells resulted in increased nuclear protein binding to the Sp1 consensus oligo by electrophoretic mobility shift assay, partly accounted for by increased binding of Sp3 (assessed by supershifting with anti-Sp3 antibody) and the by presence of a new DNA-protein complex, not shifted by anti-Sp1 or anti-Sp3 antibodies. We conclude that cigarette smoke may alter VEGF maintenance of pulmonary endothelial cells by altering VEGF and VEGF-receptor expression and signaling. The effect of cigarette smoke may be partially related to the induction of nitric oxide, since, as we have previously shown, nitric oxide can downregulate VEGF and VEGF-receptor gene expression by cultured cells in rat lungs. This interruption of VEGF maintenance of pulmonary endothelial cells by cigarette smoke may result in emphysema due to pulmonary endothelial cell death, followed by progressive disappearance of the alveolar septum by apoptosis.




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