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Type 2 Cytokines in the Pathogenesis of Sustained Airway Dysfunction and Airway Remodeling in Mice

Firestone Institute for Respiratory Health, Department of Medicine, McMaster University, Hamilton, Ontario, Canada; and Division of Molecular Bioscience, John Curtin School of Medical Research, Australian National University, Canberra, Australia

Correspondence and requests for reprints should be addressed to Mark D. Inman, M.D., Ph.D., Firestone Institute for Respiratory Health, St. Joseph's Healthcare, 50 Charlton Avenue East, Hamilton, ON, L8N 4A6 Canada. E-mail: inmanma{at}mcmaster.ca

The mechanisms underlying airway hyperresponsiveness remain unclear, although airway inflammation and remodeling likely play important roles. We have observed sustained airway hyperreactivity and airway remodeling occurring in mice after chronic allergen exposure and persisting beyond resolution of allergen-induced inflammation. The aim of this study was to delineate mechanisms involved in allergen-induced airway hyperreactivity and airway remodeling and to examine evidence for a causal association between airway remodeling and sustained airway hyperreactivity. Wild-type (WT) and interleukin (IL)-4–, IL-5–, and IL-13–deficient (-/-) mice were sensitized and studied 4 weeks after chronic allergen exposure. By measuring airway responsiveness and airway morphometry, we demonstrated that WT mice developed sustained airway hyperreactivity and aspects of airway remodeling after chronic allergen exposure. Both IL-4^-/- and IL-13^-/- mice were protected from developing sustained airway hyperreactivity and aspects of airway remodeling. In contrast, IL-5^-/- mice developed sustained airway hyperreactivity and aspects of airway remodeling similar to that seen in WT mice. Our results confirm that IL-4 and IL-13, but not IL-5, are critical for the development of sustained airway hyperreactivity and airway remodeling after allergen exposure.

Key Words: allergic disease • asthma • interleukin-4 • interleukin-5 • interleukin-13

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