Prevention of elastase-induced emphysema in placenta growth factor knock-out mice.
BACKGROUND
Although both animal and human studies suggested the association between placenta growth factor (PlGF) and chronic obstructive pulmonary disease (COPD), especially lung emphysema, the role of PlGF in the pathogenesis of emphysema remains to be clarified. This study hypothesizes that blocking PlGF prevents the development of emphysema.


METHODS
Pulmonary emphysema was induced in PlGF knock-out (KO) and wild type (WT) mice by intra-tracheal instillation of porcine pancreatic elastase (PPE). A group of KO mice was then treated with exogenous PlGF and WT mice with neutralizing anti-VEGFR1 antibody. Tumor necrosis factor alpha (TNF-alpha), matrix metalloproteinase-9 (MMP-9), and VEGF were quantified. Apoptosis measurement and immunohistochemical staining for VEGF R1 and R2 were performed in emphysematous lung tissues.


RESULTS
After 4 weeks of PPE instillation, lung airspaces enlarged more significantly in WT than in KO mice. The levels of TNF-alpha and MMP-9, but not VEGF, increased in the lungs of WT compared with those of KO mice. There was also increased in apoptosis of alveolar septal cells in WT mice. Instillation of exogenous PlGF in KO mice restored the emphysematous changes. The expression of both VEGF R1 and R2 decreased in the emphysematous lungs.


CONCLUSIONS
In this animal model, pulmonary emphysema is prevented by depleting PlGF. When exogenous PlGF is administered to PlGF KO mice, emphysema re-develops, implying that PlGF contributes to the pathogenesis of emphysema.
Cheng
Shih Lung
SL
Department of Internal Medicine, Far Eastern Memorial Hospital, Taiwan. ntuhwyh61@yahoo.com.tw
Wang
Hao Chien
HC
Yu
Chong Jen
CJ
Tsao
Po Nien
PN
Carmeliet
Peter
P
Cheng
Shi Jung
SJ
Yang
Pan Chyr
PC
D000818:Animals; D017209:Apoptosis; D004195:Disease Models, Animal; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010196:Pancreatic Elastase; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins / Q000172:deficiency* / Q000235:genetics; D011656:Pulmonary Emphysema / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
C000608036:PGF protein, human; C000608037:Pgf protein, mouse; D011257:Pregnancy Proteins; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D000072483:Placenta Growth Factor; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2; D010196:Pancreatic Elastase; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse