Persistent Effects Induced by IL-13 in the Lung

Abstract

IL-13 overexpression in the lung induces inflammatory and remodeling responses that are prominent features of asthma. Whereas most studies have concentrated on the development of IL-13-induced disease, far fewer studies have focused on the reversibility of IL-13-induced pathologies. This is particularly important because current asthma therapy appears to be poor at reversing lung remodeling. In this manuscript, we used an externally regulatable transgenic system that targets expression of IL-13 to the lung with the aim of characterizing the reversibility process. After 4 wk of doxycycline (dox) exposure, IL-13 expression resulted in mixed inflammatory cell infiltration, mucus cell metaplasia, lung fibrosis, and airspace enlargement (emphysema). After withdrawal of dox, IL-13 protein levels were profoundly reduced by 7 d and below baseline by 14 d. During this time frame, the level of lung eosinophils returned to near normal, whereas macrophages, lymphocytes, and neutrophils remained markedly elevated. IL-13-induced mucus cell metaplasia significantly decreased (91%) 3 wk after withdrawal of dox, showing strong correlation with reduced eosinophil levels. In contrast, IL-13-induced lung fibrosis did not significantly decline 4 wk after dox withdrawal. Importantly, IL-13-induced emphysema persisted, but modestly declined 4 wk after dox. Examination of transcript expression profiles identified a subset of genes that remained increased weeks after transgene expression was no longer detected. Notably, numerous IL-13-induced cytokines and enzymes were reversible (IL-6 and cathepsins), whereas others were sustained (CCL6 and chitinases) after IL-13 withdrawal, respectively. Thus, several hallmark features of IL-13-induced lung pathology persist and are dissociated from eosinophilia after IL-13 overexpression ceases.Keywords: asthma; cytokines; eosinophils; inflammation; lung Allergic asthma is characterized by chronic inflammation of the airways, airway wall remodeling, and a decline in respiratory function. In asthma, structural changes in the airway include mucus cell metaplasia, increased deposition of extracellular matrix proteins (e.g., collagen and proteoglycans), and hyperplasia of myofibroblasts and smooth muscle cells (1, 2). Airway remodeling and persistent inflammation contribute to disease pathogenesis of asthma. Animal studies have defined a critical effector role for IL-13 in many pathologic features of experimental asthma, including airway inflammation, tissue fibrosis, and mucus hypersecretion by goblet cells (3-5).The effector functions mediated by IL-13 include a diverse array of biological activities (6). IL-13-deficient animals, novel IL-13 antagonists, and transgenic overexpression modeling sys- tems have successfully defined a central role for IL-13 in some inflammatory diseases of the lung (6). In animal models, pulmonary overexpression of IL-13 results in inflammation, airway fibrosis, mucus metaplasia, airway hyperresponsiveness, and enhanced lung volumes and compliance (5, 7). The inflammatory ...

CD4+ cells are required for chronic eosinophilic lung inflammation but not airway remodeling

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