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IL-9 and IL-13 Induce Mucous Cell Metaplasia That Is Reduced by IFN- in a Bax-Mediated Pathway

¹ Department of Biological, Chemical, and Physical Sciences, Illinois Institute of Technology, Chicago, Illinois; and ² Lovelace Respiratory Research Institute, Albuquerque, New Mexico

Correspondence and requests for reprints should be addressed to Yohannes Tesfaigzi, Lovelace Respiratory Research Institute, 2425 Ridgecrest Drive, SE, Albuquerque, NM 87108. E-mail: ytesfaig{at}lrri.org

One of the major aspects of airway remodeling in asthma is the development of mucous cell metaplasia (MCM). The role of cytokines in the generation and resolution of MCM has been studied in mice and in isolated airway epithelial cells in culture. However, studies using organ cultures that keep the tubular structure of the airways intact and allow studies in the absence of inflammatory cells have not been reported. We established an organ culture system that replicates the allergen-induced MCM in mice and analyzed the role of Bax in the IFN-–induced resolution of MCM. IL-9 or IL-13 induced MCM independently, but a combined IL-9/IL-13 treatment enhanced MCM synergistically. Addition of IFN- at 0.1 ng/ml concentration further increased MCM to levels observed in allergen-exposed mice in vivo. However, MCM was reduced when explants were treated with 50 ng/ml IFN- after MCM was established. While IL-9/IL-13 induced MCM in bronchioles microdissected from bax^+/+ and bax^–/– mice to a similar extent, IFN- treatment reduced MCM only in bronchioles from bax^+/+ but not in bax^–/– bronchioles. Restoration of Bax expression in bax^–/– bronchioles using an adenoviral expression system reduced IL-9/IL-13–induced MCM while MCM was similar in noninfected or adenoviral green fluorescent protein–infected bax^–/– bronchioles. Furthermore, expressing Bax using an adenoviral expression system reduced allergen-induced MCM in mice. These studies show that allergen-induced MCM is a response to a combination of various cytokines at defined concentrations and that IFN- requires Bax for the resolution of MCM.

Key Words: lung airway cells • Th1 and Th2 cytokines • apoptosis • bronchiolar organ culture • adenoviral expression

CLINICAL RELEVANCE Our studies show that in mice, mucous cell metaplasia in an asthma setting is reduced by IFN- through a cell death regulator, Bax. Therefore, delivery of Bax to airway cells could be an effective way to reduce mucous secretions in clinical asthma.