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

Background Allergen-induced airway hyperresponsiveness (AHR) 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 aim to establish the functional connection between cholinergic stimulation and ASM contractility in different human age groups. Methods First, we employed 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 (PCLSs) from young ( 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 We have discovered that ASM hypercontraction due to cholinergic deregulation in early postnatal life requires CD38. Mechanistically, cholinergic signaling activates the PI3K/Akt 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 Our findings identify the acetylcholine-PI3K/Akt-CD38 axis as a critical mechanism of AHR in early postnatal life. Targeting this axis may provide a tailored treatment for children at high risk for allergic asthma.