Although airway hyper-responsiveness (AHR) is one of the major pathophysiological hallmarks of asthma, the precise mechanisms promoting excessive contractions of airway smooth muscle (ASM) is still poorly understood. Recent reports demonstrated that phosphoinositide 3-kinase γ (PI3Kγ) was involved in allergen-induced eosinophilic airway inflammation, AHR, and airway remodeling. Because ASM contractile hyper-responsiveness is a critical factor in asthma, Jiang et al. investigated the role of PI3Kγ to directly regulate the contractility of airway smooth muscle. Using mouse lung slices and isolated ASM, the authors demonstrated the expression of PI3Kγ in these cells and that inhibition by the selective PI3Kγ inhibitor II, but not selective inhibitors of the other PI3K family members, inhibited acetylcholine-induced ASM contraction. PI3Kγ inhibitor II only slightly reduced the initial Ca2+ transient and contraction but significantly attenuated the sustained Ca2+ oscillations and contraction following acetylcholine stimulation. This is the first report to demonstrate that PI3Kγ directly controls airway contractility through regulation of Ca2+ oscillations. Understanding the G protein-coupled receptor/PI3Kγ/Ca2+ signaling pathways in ASM may provide additional pharmacological targets for treating AHR in multiple chronic airway obstructive disorders.
See article at J Pharmacol Exp Ther 2010, 334:703–709.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics