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Published ahead of print on April 27, 2006, doi:10.1165/rcmb.2005-0474OC

Am. J. Respir. Cell Mol. Biol., Volume 35, Number 3, September 2006, 337-346

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Submitted on December 21, 2005
Revised on April 25, 2006

Persistent Effects Induced by IL-13 in the Lung

Patricia C Fulkerson1, Christine A Fischetti2, Lynn M Hassman2, Nikolaos M Nikolaidis3, and Marc E Rothenberg2*

1 Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA, 2 Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA, 3 Department of Cellular and Molecular Biology, University of Cincinnati College of Medicine, Cincinnati, OH, USA

* To whom correspondence should be addressed. E-mail: Rothenberg{at}cchmc.org.

IL-13 over-expression 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 utilized an externally regulatable transgenic system that targets expression of IL-13 to the lung with the aim of characterizing the reversibility process. Following four weeks of doxycycline (dox) exposure, IL-13 expression resulted in mixed inflammatory cell infiltration, mucus cell metaplasia, lung fibrosis and airspace enlargement (emphysema). Following withdrawal of dox, IL-13 protein levels were profoundly reduced by 7 days and below baseline by 14 days. 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 weeks after withdrawal of dox, showing strong correlation with reduced eosinophils levels. In contrast, IL-13-induced lung fibrosis did not significantly decline 4 weeks after dox withdrawal. Importantly, IL-13-induced emphysema persisted, but modestly declined 4 weeks 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) following IL-13 withdrawal, respectively. Thus, several hallmark features of IL-13-induced lung pathology persist and are dissociated from eosinophilia after IL-13 over-expression ceases.




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