Airway mucus obstruction triggers macrophage activation and matrix metalloproteinase 12-dependent emphysema.
Whereas cigarette smoking remains the main risk factor for emphysema, recent studies in β-epithelial Na(+) channel-transgenic (βENaC-Tg) mice demonstrated that airway surface dehydration, a key pathophysiological mechanism in cystic fibrosis (CF), caused emphysema in the absence of cigarette smoke exposure. However, the underlying mechanisms remain unknown. The aim of this study was to elucidate mechanisms of emphysema formation triggered by airway surface dehydration. We therefore used expression profiling, genetic and pharmacological inhibition, Foerster resonance energy transfer (FRET)-based activity assays, and genetic association studies to identify and validate emphysema candidate genes in βENaC-Tg mice and patients with CF. We identified matrix metalloproteinase 12 (Mmp12) as a highly up-regulated gene in lungs from βENaC-Tg mice, and demonstrate that elevated Mmp12 expression was associated with progressive emphysema formation, which was reduced by genetic deletion and pharmacological inhibition of MMP12 in vivo. By using FRET reporters, we show that MMP12 activity was elevated on the surface of airway macrophages in bronchoalveolar lavage from βENaC-Tg mice and patients with CF. Furthermore, we demonstrate that a functional polymorphism in MMP12 (rs2276109) was associated with severity of lung disease in CF. Our results suggest that MMP12 released by macrophages activated on dehydrated airway surfaces may play an important role in emphysema formation in the absence of cigarette smoke exposure, and may serve as a therapeutic target in CF and potentially other chronic lung diseases associated with airway mucus dehydration and obstruction.
1 Department of Translational Pulmonology, and.
Joanna B
JB
Trojanek
Amanda
A
Cobos-Correa
Stefanie
S
Diemer
Michael
M
Kormann
Susanne C
SC
Schubert
Zhe
Z
Zhou-Suckow
Raman
R
Agrawal
Julia
J
Duerr
Claudius J
CJ
Wagner
Jolanthe
J
Schatterny
Stephanie
S
Hirtz
Olaf
O
Sommerburg
Dominik
D
Hartl
Carsten
C
Schultz
Marcus A
MA
Mall
D000402:Airway Obstruction / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D003550:Cystic Fibrosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D003681:Dehydration / Q000276:immunology / Q000378:metabolism; D023281:Genomics; D008262:Macrophage Activation / Q000276:immunology*; D016676:Macrophages, Alveolar / Q000276:immunology* / Q000378:metabolism; D053508:Matrix Metalloproteinase 12 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D018345:Mice, Knockout; D009093:Mucus / Q000276:immunology* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D029424:Pulmonary Disease, Chronic Obstructive / Q000276:immunology / Q000378:metabolism; D011656:Pulmonary Emphysema / Q000276:immunology* / Q000378:metabolism; D050800:STAT6 Transcription Factor / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology
D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D053508:Matrix Metalloproteinase 12
airway surface liquid; chronic obstructive pulmonary disease; cystic fibrosis; inflammation; mucus