title: Targeting phosphoinositide 3-kinase γ in airway smooth muscle cells to suppress interleukin-13-induced mouse airway hyperresponsiveness.
abstract: We recently reported that phosphoinositide 3-kinase γ (PI3Kγ) directly regulates airway smooth muscle (ASM) contraction by modulating Ca(2+) oscillations. Because ASM contraction plays a critical role in airway hyperresponsiveness (AHR) of asthma, the aim of the present study was to determine whether targeting PI3Kγ in ASM cells could suppress AHR in vitro and in vivo. Intranasal administration into mice of interleukin-13 (IL-13; 10 μg per mouse), a key pathophysiologic cytokine in asthma, induced AHR after 48 h, as assessed by invasive tracheostomy. Intranasal administration of a broad-spectrum PI3K inhibitor or a PI3Kγ-specific inhibitor 1 h before AHR assessment attenuated IL-13 effects. Airway responsiveness to bronchoconstrictor agonists was also examined in precision-cut mouse lung slices pretreated without or with IL-13 for 24 h. Acetylcholine and serotonin dose-response curves indicated that IL-13-treated lung slices had a 40 to 50% larger maximal airway constriction compared with controls. Furthermore, acetylcholine induced a larger initial Ca(2+) transient and increased Ca(2+) oscillations in IL-13-treated primary mouse ASM cells compared with control cells, correlating with increased cell contraction. As expected, PI3Kγ inhibitor treatment attenuated IL-13-augmented airway contractility of lung slices and ASM cell contraction. In both control and IL-13-treated ASM cells, small interfering RNA-mediated knockdown of PI3Kγ by 70% only reduced the initial Ca(2+) transient by 20 to 30% but markedly attenuated Ca(2+) oscillations and contractility of ASM cells by 50 to 60%. This report is the first to demonstrate that PI3Kγ in ASM cells is important for IL-13-induced AHR and that acute treatment with a PI3Kγ inhibitor can ameliorate AHR in a murine model of asthma.
authors.affiliation: Department of Pharmacology, Creighton University School of Medicine, 2500 California Plaza, Omaha, NE 68178, USA.
authors.forename: Haihong
authors.initials: H
authors.lastname: Jiang
authors.forename: Yan
authors.initials: Y
authors.lastname: Xie
authors.forename: Peter W
authors.initials: PW
authors.lastname: Abel
authors.forename: Myron L
authors.initials: ML
authors.lastname: Toews
authors.forename: Robert G
authors.initials: RG
authors.lastname: Townley
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Casale
authors.forename: Yaping
authors.initials: Y
authors.lastname: Tu
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001249:Asthma / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D016535:Bronchial Hyperreactivity / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D058544:Class Ib Phosphatidylinositol 3-Kinase / Q000235:genetics / Q000378:metabolism*; D018793:Interleukin-13 / Q000276:immunology* / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009119:Muscle Contraction / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D009130:Muscle, Smooth / Q000276:immunology / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D012701:Serotonin / Q000494:pharmacology; D014132:Trachea / Q000187:drug effects / Q000276:immunology / Q000378:metabolism
chemical_list: D018793:Interleukin-13; D000081082:Phosphoinositide-3 Kinase Inhibitors; D012701:Serotonin; D058544:Class Ib Phosphatidylinositol 3-Kinase; C546764:Pik3cg protein, mouse; D000109:Acetylcholine; D002118:Calcium