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 pulmonar y disease (COPD). However, only a minority of smokers develop significant C OPD, and patients with asthma or asthma-like airway hyperresponsiveness or eosinophilia experience accelerated loss of lung function after cigarette s moke exposure. Pulmonary inflammation is a characteristic feature of lungs from patients with COPD. Surprisingly, the mediators of this inflammation a nd their contributions to the pathogenesis and varied natural history of CO PD are not well defined. Here we show that IL-13, a critical cytokine in as thma, causes emphysema with enhanced lung volumes and compliance, mucus met aplasia, 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 i nduced by IL-13 in this setting. Zn addition, treatment with MMP or cystein e proteinase antagonists significantly decreased the emphysema and inflamma tion, 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- a nd cathepsin-dependent mechanism(s) and highlight common mechanisms that ma y underlie COPD and asthma.