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

By T. Zheng, Zhou Zhu, Zhongde Wang, R. Homer, B. Ma, R. Riese, H. Chapman, S. Shapiro, Jack A. Elias. Journal of Clinical Investigation, 2000

663 citations recorded by the source corpus.

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.

Subfields: Physiology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/4cbcc22e5a45c59002849d31859aba3281b69012

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In Physiology

1. P. Barnes
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In Pulmonary and Respiratory Medicine

1. P. Noble
2. P. Barnes
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Citations in the corpus

• Direct effects of interleukin-13 on epithelial cells cause airway hyperreactivity and mucus overproduction in asthma (2002, background): “Overproduction of IL-13 in the lung also causes emphysem”
• Interleukin‐13 in asthma pathogenesis (2004, background): “Corry DB, et al. Overlapping and independent contributions of MMP2 and MMP9 to lung allergic inflammatory cell regression through decreased CC chemokines.”
• Mediators of Chronic Obstructive Pulmonary Disease (2004, background): “Overexpression of IL-13 and also interferon- in murine lungs unexpectedly results in emphysema that is mediated by increased expression of MMPs and cathepsins (Wang et al., 2000; Zheng et al., 2000).”
• Association of the IL-13 polymorphisms rs1800925 and rs20541 with chronic obstructive pulmonary disease risk (2017, background): “In vivo studies showed that the overexpression of IL-13 in the adult murine lung caused a phenotype that mirrored human COPD with prominent emphysema.([4]) These lines of evidence suggested that IL-13 was implicated in the pathogenesis of COPD and genetic variations in the IL-13 gene may modify the ”
• Pathogenesis of chronic obstructive pulmonary disease. (2005, background): “In such mice, emphysema induced by IL-13 or IFNexpression is also reduced (48), associated with a marked reduction in monocyte recruitment to the lungs.”
• Interleukin-13 Induces Tissue Fibrosis by Selectively Stimulating and Activating Transforming Growth Factor β1 (2001, methodology): “mRNA levels were assessed using reverse transcription (RT)-PCR and ribonuclease protection assays as described previously by our laboratories (33, 37).”