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Adenovirus IL-13–Induced Airway Disease in Mice

A Corticosteroid-Resistant Model of Severe Asthma

Alex G. Therien^1,2,*, Virginie Bernier^3,*,, Sean Weicker³, Paul Tawa¹, Jean-Pierre Falgueyret¹, Marie-Claude Mathieu¹, Jeanne Honsberger³, Véronique Pomerleau¹, Annette Robichaud^3,¶, Rino Stocco¹, Lynn Dufresne³, Hani Houshyar³, Josiane Lafleur³, Chidambaram Ramachandran^1,, Gary P. O'Neill^1,3, Deborah Slipetz³ and Christopher M. Tan³

Departments of ³ Pharmacology and ¹ Biochemistry and Molecular Biology, Merck Frosst Center for Therapeutic Research, Kirkland, Quebec, Canada; and ² Department of Biochemistry, McGill University, Montreal, Quebec, Canada

Correspondence and requests for reprints should be addressed to Christopher M. Tan, Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Highway, Kirkland, PQ, H9H 3L1 Canada. E-mail: christopher_tan{at}merck.com

Interleukin 13 (IL-13) is considered to be a key driver of the development of airway allergic inflammation and remodeling leading to airway hyperresponsiveness (AHR). How precisely IL-13 leads to the development of airway inflammation, AHR, and mucus production is not fully understood. In order to identify key mediators downstream of IL-13, we administered adenovirus IL-13 to specifically induce IL-13–dependent inflammation in the lungs of mice. This approach was shown to induce cardinal features of lung disease, specifically airway inflammation, elevated cytokines, AHR, and mucus secretion. Notably, the model is resistant to corticosteroid treatment and is characterized by marked neutrophilia, two hallmarks of more severe forms of asthma. To identify IL-13–dependent mediators, we performed a limited-scale two-dimensional SDS-PAGE proteomic analysis and identified proteins significantly modulated in this model. Intriguingly, several identified proteins were unique to this model, whereas others correlated with those modulated in a mouse ovalbumin-induced pulmonary inflammation model. We corroborated this approach by illustrating that proteomic analysis can identify known pathways/mediators downstream of IL-13. Thus, we have characterized a murine adenovirus IL-13 lung model that recapitulates specific disease traits observed in human asthma, and have exploited this model to identify effectors downstream of IL-13. Collectively, these findings will enable a broader appreciation of IL-13 and its impact on disease pathways in the lung.

Key Words: IL-13 • proteomic • asthma • neutrophils • corticosteroids

CLINICAL RELEVANCE This research details a novel, IL-13–dependent, steroid-resistant model of lung inflammation in mice that may facilitate the identification of druggable effectors, pathways, and/or biomarkers relevant for the treatment of steroid-resistant human asthma.