A distinctive alveolar macrophage activation state induced by cigarette smoking.
BACKGROUND
Macrophages are believed to play a central role in emphysema based largely on data from mouse models. However, the relevance of these models to smoking-related lung disease in humans is uncertain.


OBJECTIVE
We sought to comprehensively characterize the effects of smoking on gene expression in human alveolar macrophages and to compare these with effects seen in transgenic mouse models of emphysema.


METHODS
We used DNA microarrays with genomewide coverage to analyze alveolar macrophages from 15 smokers, 15 nonsmokers, and 15 subjects with asthma (disease control). Selected gene expression changes were validated by polymerase chain reaction and ELISA. Expression changes were compared with those identified by microarray analysis of interleukin-13-overexpressing and integrin-beta6-deficient mice, which both develop emphysema.


RESULTS
All 15 smokers shared a common pattern of macrophage gene expression that distinguished them from nonsmokers, a finding not observed in subjects with asthma. We identified 110 genes as differentially expressed in smokers despite using conservative statistical methods. Matrix metalloproteinase 12, a proteinase that plays a critical role in mouse models, was the third most highly induced gene in smokers (ninefold, p < 0.0001). However, most changes in smokers were not reflected in mouse models. One such finding was increased osteopontin expression in smokers (fourfold, p = 0.006), which was confirmed at the protein level and correlated with the degree of airway obstruction.


CONCLUSIONS
Smoking induces a remarkably consistent and distinctive pattern of alveolar macrophage activation. These studies identify aspects of mouse models that are directly relevant to human smokers and also reveal novel potential mediators of smoking-related diseases.
Woodruff
Prescott G
PG
UCSF-Mission Bay Rock Hall, Room 545, 1550 4th Street, San Francisco, CA 94158, USA. laura.koth@ucsf.edu
Koth
Laura L
LL
Yang
Yee Hwa
YH
Rodriguez
Madeleine W
MW
Favoreto
Silvio
S
Dolganov
Gregory M
GM
Paquet
Agnes C
AC
Erle
David J
DJ
D000328:Adult; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015870:Gene Expression; D006801:Humans; D008262:Macrophage Activation / Q000235:genetics*; D016676:Macrophages, Alveolar / Q000378:metabolism*; D008297:Male; D053508:Matrix Metalloproteinase 12; D008666:Metalloendopeptidases / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011656:Pulmonary Emphysema / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D012313:RNA / Q000235:genetics*; D012907:Smoking / Q000009:adverse effects / Q000235:genetics / Q000378:metabolism*
D012313:RNA; D008666:Metalloendopeptidases; C507122:MMP12 protein, human; D053508:Matrix Metalloproteinase 12