Imbalance of apoptosis and cell proliferation contributes to the development and persistence of emphysema.
BACKGROUND
We postulate that in adults there is an established lung structure maintenance program and that lung alveolar septal cells are undergoing both continuous apoptosis and proliferation. Whereas lung cell apoptosis has been recognized in human emphysema, little is known about cell proliferation.


METHODS
Using a novel rat model of emphysema, induced by intratracheal instillation of cigarette smoke extract (CSE), we investigated the dynamics of emphysematous lung destruction. Emphysematous lung destruction was determined by measuring mean linear intercept and destructive index. Lung injury and repair were assessed by immunohistochemistry and Western blot analysis for active caspase-3 and proliferating cell nuclear antigen (PCNA) after 4, 8, and 12 weeks of CSE instillations.


RESULTS
The emphysematous lung tissue destruction was present at 4 weeks of CSE treatment and progressed to 8 weeks. Spontaneous repair began at 12 weeks. Treatment with a peroxisome proliferator activated receptor (PPAR)α+γ agonist or granulocyte and macrophage-colony stimulating factor (GM-CSF) for 4 weeks prevented the progression of emphysematous lung destruction and decreased the number of caspase-3-positive cells.


CONCLUSIONS
Apoptosis and cell proliferation occur in this new model of emphysema. Treatment with a PPARα+γ agonist or GM-CSF can inhibit the progression of emphysematous alveolar septal destruction by decreasing alveolar cell apoptosis.
Division of Pulmonary Science and Critical Care Medicine, University of Colorado School of Medicine, Denver, CO 80262, USA. plmjhlee@yahoo.co.kr
Ji-Hyun
JH
Lee
Masayuki
M
Hanaoka
Yoshiaki
Y
Kitaguchi
Donatas
D
Kraskauskas
Leland
L
Shapiro
Norbert F
NF
Voelkel
Laima
L
Taraseviciene-Stewart
D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004646:Emphysema / Q000139:chemically induced / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D020778:Matrix Metalloproteinase 2 / Q000187:drug effects / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000187:drug effects / Q000378:metabolism; D047493:PPAR alpha / Q000819:agonists; D047495:PPAR gamma / Q000819:agonists; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000378:metabolism / Q000473:pathology; D051381:Rats; D012906:Smoke; D014026:Nicotiana; D042461:Vascular Endothelial Growth Factor A / Q000187:drug effects / Q000378:metabolism; D000515:alpha 1-Antitrypsin / Q000494:pharmacology
D047493:PPAR alpha; D047495:PPAR gamma; D018809:Proliferating Cell Nuclear Antigen; D012906:Smoke; D042461:Vascular Endothelial Growth Factor A; D000515:alpha 1-Antitrypsin; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D053148:Caspase 3; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9