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.
Bibliographical noteFunding Information:
This work was supported by National Institutes of Health grants K08135443 (Y.B.), 1R01HL132991 (X.A.), and R21HL151695 (R.K.).
© 2021 American Academy of Allergy, Asthma & Immunology
- Airway smooth muscle
- airway hyperresponsiveness
- childhood asthma
- cholinergic innervation
- precision-cut lung slice
PubMed: MeSH publication types
- Journal Article
- Research Support, N.I.H., Extramural