Persistent effects induced by IL-13 in the lung

PC Fulkerson, CA Fischetti, LM Hassman… - American journal of …, 2006 - atsjournals.org
PC Fulkerson, CA Fischetti, LM Hassman, NM Nikolaidis, ME Rothenberg
American journal of respiratory cell and molecular biology, 2006atsjournals.org
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 …
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.
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