Corticosteroid-resistant neutrophilic airway inflammation and hyperresponsiveness caused by IL-13

Effective treatment for severe corticosteroid refractory asthma is a significant unmet clinical need. It affects only a small percent of the asthmatic population but accounts for a disproportionate use of healthcare resources. The aim was to study IL-13 transgenic mice to test the hypothesis that a subset of IL-13 mediated airway responses are corticosteroid-unresponsive and contribute to ongoing airways symptoms.IL-13 expression in the lungs was induced using Doxycycline in Ccsp-rtTA/Otet-Il-13 (Ccsp/Il-13) mice. Where indicated, mice received intra-peritoneal injections of 3mg/kg Dexamethasone for 3-7 days. Lungs were analysed for airway hyperreactivity and inflammation.Compared to controls, Ccsp/Il-13 mice showed significantly increased airway hyperresponsiveness (AHR) to methacholine and immunohistochemistry revealed increased bronchial smooth muscle and goblet cell metaplasia. The bronchoalveolar lavage fluid contained mixed eosinophilic and neutrophilic inflammation, but neutrophils predominated. Characteristic Th2-responsive genes as well as genes associated with Th17 responses were significantly elevated. Treatment with steroids did not abrogate AHR, even though eosinophilia and the ‘Th2’ gene signature were significantly reduced. Neutrophils and the ‘Th17’ signature remained elevated.Although IL-13 promotes eosinophilic airways disease, it can also drive corticosteroid refractory inflammation characterised by persistent neutrophilia, Th17 cytokines and maintenance of AHR. The Ccsp/Il-13 mouse may be a useful model for dissecting the molecular pathways and mechanisms associated with predominant neutrophilic, corticosteroid refractory airway disease