Inducible targeting of IL-13 to the adult lung causes matrix metalloproteinase- and cathepsin-dependent emphysema.
Cigarette smoke exposure is the major cause of chronic obstructive pulmonary disease (COPD). However, only a minority of smokers develop significant COPD, and patients with asthma or asthma-like airway hyperresponsiveness or eosinophilia experience accelerated loss of lung function after cigarette smoke exposure. Pulmonary inflammation is a characteristic feature of lungs from patients with COPD. Surprisingly, the mediators of this inflammation and their contributions to the pathogenesis and varied natural history of COPD are not well defined. Here we show that IL-13, a critical cytokine in asthma, causes emphysema with enhanced lung volumes and compliance, mucus metaplasia, and inflammation, when inducibly overexpressed in the adult murine lung. MMP-2, -9, -12, -13, and -14 and cathepsins B, S, L, H, and K were induced by IL-13 in this setting. In addition, treatment with MMP or cysteine proteinase antagonists significantly decreased the emphysema and inflammation, but not the mucus in these animals. These studies demonstrate that IL-13 is a potent stimulator of MMP and cathepsin-based proteolytic pathways in the lung. They also demonstrate that IL-13 causes emphysema via a MMP- and cathepsin-dependent mechanism(s) and highlight common mechanisms that may underlie COPD and asthma.
Zheng
T
T
Section of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520-8057, USA.
Zhu
Z
Z
Wang
Z
Z
Homer
R J
RJ
Ma
B
B
Riese
R J
RJ
Chapman
H A
HA
Shapiro
S D
SD
Elias
J A
JA
D000818:Animals; D001249:Asthma / Q000150:complications; D001483:Base Sequence; D002403:Cathepsins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D004646:Emphysema / Q000201:enzymology* / Q000209:etiology* / Q000276:immunology; D006801:Humans; D018793:Interleukin-13 / Q000235:genetics / Q000378:metabolism*; D008168:Lung / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D008173:Lung Diseases, Obstructive / Q000201:enzymology / Q000209:etiology / Q000276:immunology; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D011480:Protease Inhibitors / Q000494:pharmacology; D012907:Smoking / Q000009:adverse effects
D017931:DNA Primers; D018793:Interleukin-13; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D002403:Cathepsins; D020782:Matrix Metalloproteinases