Inducible targeting of IL-13 to the adult lung causes matrix metalloproteinase– and cathepsin-dependent emphysema

TLDR

Cigarette smoke is the main cause of COPD, yet only a minority of smokers develop the disease, and patients with asthma or eosinophilia experience accelerated lung function loss, highlighting that the inflammatory mediators driving COPD remain poorly defined. Inducible overexpression of IL‑13 in adult mouse lungs induces emphysema, mucus metaplasia, and inflammation through upregulation of MMPs and cathepsins, and pharmacologic inhibition of these proteases attenuates emphysema and inflammation, demonstrating that IL‑13 drives emphysema via MMP‑ and cathepsin‑dependent pathways that may link COPD and asthma.

Abstract

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.