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Targeting phosphoinositide 3‐kinase γ in airway smooth muscle cells to suppress interleukin‐13‐induced mouse airway hyperresponsiveness
Author(s) -
Jiang Haihong,
Xie Yan,
Abel Peter W.,
Toews Myron L.,
Townley Robert G.,
Casale Thomas B.,
Tu Yaping
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.667.4
Subject(s) - phosphoinositide 3 kinase , medicine , pi3k/akt/mtor pathway , g protein coupled receptor , contractility , immunology , receptor , signal transduction , pharmacology , endocrinology , microbiology and biotechnology , biology
Excessive activation of different bronchoconstrictor G‐protein coupled receptors (GPCRs) in airway smooth muscle (ASM) contributes to airway hyperresponsiveness (AHR), the pathophysiologic hallmark of asthma. We previously reported that phosphoinositide 3‐kinase γ (PI3Kγ), a down‐stream effector of multiple types of GPCRs, directly regulates ASM contraction by modulating Ca 2+ oscillations. The aim of this study was to determine whether targeting PI3Kγ in ASM cells could suppress AHR induced by interleukin‐13 (IL‐13) in a murine model of asthma. We found that intranasal administration of IL‐13 into mice induced AHR after 48 h, as assessed by invasive tracheostomy. Acute treatment with a PI3Kγ‐specific inhibitor attenuated IL‐13 effects in vivo and IL‐13‐augmented airway contractility of precision‐cut mouse lung slices in vitro . In addition, silencing PI3Kγ expression in isolated mouse ASM cells markedly attenuated IL‐13‐augmented Ca 2+ oscillations and contractility of ASM cells induced by different bronchoconstrictor GPCRs. Our studies demonstrate that PI3Kγ in ASM cells is important for AHR and acute treatment with a PI3Kγ inhibitor can ameliorate AHR by a broader‐based suppression of unwanted GPCR signaling in a murine model of asthma. This work was supported by American Asthma Foundation Early Excellence Award and State of Nebraska Research Funds.