Increased surfactant protein-D and foamy macrophages in smoking-induced mouse emphysema.
OBJECTIVE
The molecular mechanisms underlying COPD remain undetermined. The lungs of surfactant protein-D (SP-D) deficient mice show emphysema and an excessive number of foamy macrophages. This study aims to elucidate roles of SP-D and foamy macrophages in smoking-induced mouse emphysema.


METHODS
Twenty B6C3F1 mice were exposed to cigarette smoke (2 cigarettes/day/mouse for 6 months). The mice were killed, and formalin-fixed, paraffin-embedded lung sections were carried out on seven mice, BAL was carried out on six mice, and seven mice were used to make lung homogenates. In in vitro studies, A549 cells were transduced with the SP-D expression plasmid and treated with cigarette smoke extract to evaluate cell viability.


RESULTS
Emphysema was induced in the mice by chronic cigarette smoke exposure. Increased expression of matrix metalloproteinase-9 and -12 was observed, and foamy alveolar macrophages accumulated in the smoke-exposed lungs. Immunostaining of BAL cells revealed the major source of matrix metalloproteinase-12 to be foamy alveolar macrophages. Furthermore, SP-D was elevated in emphysema lungs. Expression of transcription factors, Fra-1, junB and C/EBPbeta (which induce SP-D) were significantly elevated in emphysema lungs. The in vitro expression of SP-D gene in A549 cells prolonged cell survival following exposure to cigarette smoke condensate.


CONCLUSIONS
The accumulation of foamy alveolar macrophages may play a key role in the development of smoking-induced emphysema. Increased SP-D may play a protective role in the development of smoking-induced emphysema, in part by preventing alveolar cell death.
Hirama
Noriyuki
N
Department of Cardiology, Pulmonology, and Nephrology, Course of Internal Medicine and Therapeutics, Yamagata University School of Medicine, Yamagata, Japan.
Shibata
Yoko
Y
Otake
Kazuhisa
K
Machiya
Jun-ichi
J
Wada
Toshihiro
T
Inoue
Sumito
S
Abe
Shuichi
S
Takabatake
Noriaki
N
Sata
Makoto
M
Kubota
Isao
I
D000818:Animals; D015153:Blotting, Western; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D004195:Disease Models, Animal; D024202:Electrophoretic Mobility Shift Assay; D004797:Enzyme-Linked Immunosorbent Assay; D015870:Gene Expression; D007150:Immunohistochemistry; D016676:Macrophages, Alveolar / Q000378:metabolism / Q000473:pathology*; D008297:Male; D053508:Matrix Metalloproteinase 12 / Q000378:metabolism; D051379:Mice; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics; D011656:Pulmonary Emphysema / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D037663:Pulmonary Surfactant-Associated Protein D / Q000235:genetics / Q000378:metabolism*; D012313:RNA / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012907:Smoking / Q000009:adverse effects*; D000099169:Fos-Related Antigen 1
D053508:Matrix Metalloproteinase 12; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D037663:Pulmonary Surfactant-Associated Protein D; D012313:RNA; D000099169:Fos-Related Antigen 1