CD38 plays an age-related role in cholinergic deregulation of airway smooth muscle contractility

Background: Allergen-induced airway hyperresponsiveness in neonatal mice, but not adult mice, is caused by elevated innervation and consequent cholinergic hyperstimulation of airway smooth muscle (ASM). Whether this inflammation-independent mechanism contributes to ASM hypercontraction in childhood asthma warrants investigation. Objective: We aimed to establish the functional connection between cholinergic stimulation and ASM contractility in different human age groups. Methods: First, we used a neonatal mouse model of asthma to identify age-related mediators of cholinergic deregulation of ASM contractility. Next, we conducted validation and mechanistic studies in primary human ASM cells and precision-cut lung slices from young (<5 years old) and adult (>20 years old) donor lungs. Finally, we evaluated the therapeutic potential of the identified cholinergic signaling mediators using culture models of human ASM hypercontraction. Results: ASM hypercontraction due to cholinergic deregulation in early postnatal life requires CD38. Mechanistically, cholinergic signaling activates the phosphatidylinositol 3-kinase/protein kinase B pathway in immature ASM cells to upregulate CD38 levels, thereby augmenting the Ca²⁺ response to contractile agonists. Strikingly, this early-life, CD38-mediated ASM hypercontraction is not alleviated by the β-agonist formoterol. Conclusions: The acetylcholine–phosphatidylinositol 3-kinase/protein kinase B–CD38 axis is a critical mechanism of airway hyperresponsiveness in early postnatal life. Targeting this axis may provide a tailored treatment for children at high risk for allergic asthma.