Endothelial Cell Death and Decreased Expression of Vascular Endothelial Growth Factor and Vascular Endothelial Growth Factor Receptor 2 in Emphysema

• Published in: American journal of respiratory and critical care medicine Vol. 163; no. 3; pp. 737 - 744
• Main Authors: KASAHARA, YASUNORI, TUDER, RUBIN M., COOL, CARLYNE D., LYNCH, DAVID A., FLORES, SONIA C., VOELKEL, NORBERT F.
• Format: Journal Article
• Language: English
• Published: New York, NY American Lung Association 01.03.2001
• Subjects: Adolescent; Adult; Aged; Apoptosis; Biological and medical sciences; Chronic obstructive pulmonary disease, asthma; Emphysema - genetics; Emphysema - metabolism; Emphysema - pathology; Endothelial Growth Factors - analysis; Endothelial Growth Factors - biosynthesis; Female; Humans; In Situ Nick-End Labeling; Lymphokines - analysis; Lymphokines - biosynthesis; Male; Medical sciences; Middle Aged; Pneumology; Receptor, Epidermal Growth Factor - analysis; Receptor, Epidermal Growth Factor - biosynthesis; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors; Human; Lung disease; Vascular endothelium growth factor; Respiratory disease; Pathogenesis; Bronchus disease; Obstructive pulmonary disease; Gene expression; Emphysema; Growth factor; Biological receptor
• ISSN: 1073-449X; 1535-4970
• DOI: 10.1164/ajrccm.163.3.2002117

Emphysema due to cigarette smoking is characterized by a loss of alveolar structures. We hypothesize that the disappearance of alveoli involves apoptosis of septal endothelial cells and a decreased expression of lung vascular endothelial growth factor (VEGF) and its receptor 2 (VEGF R2). By terminal transferase dUTP nick end labeling (TUNEL) in combination with immunohistochemistry, we found that the number of TUNEL+ septal epithelial and endothelial cells/lung tissue nucleic acid (microg) was increased in the alveolar septa of emphysema lungs (14.2 +/- 2.0/microg, n = 6) when compared with normal lungs (6.8 +/- 1.3/microg, n = 7) (p < 0.01) and with primary pulmonary hypertensive lungs (2.3 +/- 0.8/microg, n = 5) (p < 0.001). The cell death events were not significantly different between healthy nonsmoker (7.4 +/- 1.9/microg) and smoker (5.7 +/- 0.7/microg) control subjects. The TUNEL results were confirmed by single-stranded DNA and active caspase-3 immunohistochemistry, and by DNA ligation assay. Emphysema lungs (n = 12) had increased levels of oligonucleosomal-length DNA fragmentation when compared with normal lungs (n = 11). VEGF, VEGF R2 protein, and mRNA expression were significantly reduced in emphysema. We propose that epithelial and endothelial alveolar septal death due to a decrease of endothelial cell maintenance factors may be part of the pathogenesis of emphysema.