PI3Kγ-deficient mice have reduced levels of allergen-induced eosinophilic inflammation and airway remodeling

Lim DH, Cho JY, Song DJ, Lee SY, Miller M, Broide DH. PI3K gamma-deficient mice have reduced levels of allergen-induced eosinophilic inflammation and airway remodeling. Am J Physiol Lung Cell Mol Physiol 296: L210-L219, 2009. First published November 21, 2008; doi:10.1152/ajplung.90275.2008.-In this study, we have examined the role of phosphoinositide 3 kinase gamma (PI3K gamma), a class Ib PI3K, in contributing to airway remodeling utilizing PI3K gamma-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 gamma-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 gamma-deficient mice, suggesting that trafficking of eosinophils into the lung was reduced in PI3K gamma-deficient mice. PI3K gamma-deficient and WT mice had similar levels of IL-5 and eotaxin-1. The reduced eosinophil recruitment to the airway in PI3K gamma-deficient mice challenged with OVA was associated with significantly reduced numbers of TGF-beta 1 + 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 alpha-smooth muscle staining was significantly reduced in PI3K gamma-deficient compared with WT mice. Overall, this study demonstrates an important role for PI3K gamma in mediating allergen-induced eosinophilic airway inflammation and airway remodeling, suggesting that PI3K gamma may be a novel therapeutic target in asthma.