Phosphoinositide 3-Kinase Regulates Airway Smooth Muscle Contraction by Modulating Calcium Oscillations

Phosphoinositide 3-kinase (PI3K ) has been implicated in the pathogenesis of asthma, but its mechanism has been considered indirect, through release of inflammatory cell mediators. Because airway smooth muscle (ASM) contractile hyper-responsiveness plays a critical role in asthma, the aim of the present study was to determine whether PI3K can directly regulate contractility of ASM. Immunohistochemistry staining indicated expression of PI3K protein in ASM cells of mouse trachea and lung, which was confirmed by Western blot analysis in isolated mouse tracheal ASM cells. PI3K inhibitor II inhibited acetylcholine (ACh)-stimulated airway contraction of cultured precision-cut mouse lung slices in a dose-dependent manner with 75% inhibition at 10 M. In contrast, inhibitors of PI3K , PI3K , or PI3K , at concentrations 40-fold higher than their reported IC50 values for their primary targets, had no effect. It is noteworthy that airways in lung slices pretreated with PI3K inhibitor II still exhibited an ACh-induced initial contraction, but the sustained contraction was significantly reduced. Furthermore, the PI3K -selective inhibitor had a small inhibitory effect on the ACh-stimulated initial Ca transient in ASM cells of mouse lung slices or isolated mouse ASM cells but significantly attenuated the sustained Ca oscillations that are critical for sustained airway contraction. This report is the first to show that PI3K directly controls contractility of airways through regulation of Ca oscillations in ASM cells. Thus, in addition to effects on airway inflammation, PI3K inhibitors may also exert direct effects on the airway contraction that contribute to pathologic airway hyper-responsiveness.