biostudies-literatureBai YNHLBI NIH HHSNational Institutes of Health1643-1654.e8https://www.ebi.ac.uk/biostudies/studies/S-EPMC9081122biostudies-literatureUnknown149(5)<h4>Background</h4>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.<h4>Objective</h4>We aimed to establish the functional connection between cholinergic stimulation and ASM contractility in different human age groups.<h4>Methods</h4>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.<h4>Results</h4>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.<h4>Conclusions</h4>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.The Journal of allergy and clinical immunologyCD38 plays an age-related role in cholinergic deregulation of airway smooth muscle contractility.PMC9081122R01 HL1329911R01HL132991K08135443R21HL151695R21 HL112619K08 HL135443Bai YGuedes AGPKrishnan RAi XfalseCD38 plays an age-related role in cholinergic deregulation of airway smooth muscle contractility.<h4>Background</h4>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.<h4>Objective</h4>We aimed to establish the functional connection between cholinergic stimulation and ASM contractility in different human age groups.<h4>Methods</h4>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.<h4>Results</h4>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.<h4>Conclusions</h4>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.2022-01-01T00:00:00Z2022 May2025-04-19T22:59:26.86Z2025-04-19T22:59:26.86ZS-EPMC90811223480043110.1016/j.jaci.2021.10.033