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PI3K-deficient mice have reduced levels of allergen-induced eosinophilic inflammation and airway remodeling

Department of Medicine, University of California San Diego, San Diego, California

Submitted 15 April 2008 ; accepted in final form 18 November 2008

In this study, we have examined the role of phosphoinositide 3 kinase (PI3K), a class Ib PI3K, in contributing to airway remodeling utilizing PI3K-deficient mice exposed to chronic allergen challenge. Wild-type (WT) mice sensitized to ovalbumin (OVA) and chronically challenged with OVA for 1 mo developed significantly increased levels of eosinophilic inflammation and airway remodeling. In contrast, PI3K-deficient mice challenged with OVA had significantly reduced numbers of bronchoalveolar lavage and peribronchial eosinophils compared with WT mice. There was no significant difference in the number of bone marrow or circulating peripheral blood eosinophils when comparing WT mice and PI3K-deficient mice, suggesting that trafficking of eosinophils into the lung was reduced in PI3K-deficient mice. PI3K-deficient and WT mice had similar levels of IL-5 and eotaxin-1. The reduced eosinophil recruitment to the airway in PI3K-deficient mice challenged with OVA was associated with significantly reduced numbers of TGF-β1+ peribronchial cells, reduced numbers of pSmad 2/3+ airway epithelial cells, and pSmad 2/3+ peribronchial cells, as well as significantly reduced levels of peribronchial fibrosis (quantitated by trichrome staining and image analysis as well as by lung collagen levels). In addition, the area of peribronchial -smooth muscle staining was significantly reduced in PI3K-deficient compared with WT mice. Overall, this study demonstrates an important role for PI3K in mediating allergen-induced eosinophilic airway inflammation and airway remodeling, suggesting that PI3K may be a novel therapeutic target in asthma.

transforming growth factor-β1; pSmad2/3; smooth muscle; mucus

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