Endothelial cell death and decreased expression of vascular endothelial growth factor and vascular endothelial growth factor receptor 2 in emphysema.
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.
Division of Pulmonary Sciences and Critical Care Medicine, Pulmonary Hypertension Center, Department of Pathology, and Webb-Waring Antioxidant Research Institute, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA.
Y
Y
Kasahara
R M
RM
Tuder
C D
CD
Cool
D A
DA
Lynch
S C
SC
Flores
N F
NF
Voelkel
D000293:Adolescent; D000328:Adult; D000368:Aged; D017209:Apoptosis; D004646:Emphysema / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D016228:Endothelial Growth Factors / Q000032:analysis / Q000096:biosynthesis*; D066246:ErbB Receptors / Q000032:analysis / Q000096:biosynthesis*; D005260:Female; D006801:Humans; D020287:In Situ Nick-End Labeling; D008222:Lymphokines / Q000032:analysis / Q000096:biosynthesis*; D008297:Male; D008875:Middle Aged; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D008222:Lymphokines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D066246:ErbB Receptors