{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Bai Y"],"funding":["NHLBI NIH HHS","National Institutes of Health"],"pagination":["1643-1654.e8"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC9081122"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["149(5)"],"pubmed_abstract":["<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 Ca<sup>2+</sup> 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."],"journal":["The Journal of allergy and clinical immunology"],"pubmed_title":["CD38 plays an age-related role in cholinergic deregulation of airway smooth muscle contractility."],"pmcid":["PMC9081122"],"funding_grant_id":["R01 HL132991","1R01HL132991","K08135443","R21HL151695","R21 HL112619","K08 HL135443"],"pubmed_authors":["Bai Y","Guedes AGP","Krishnan R","Ai X"],"additional_accession":[]},"is_claimable":false,"name":"CD38 plays an age-related role in cholinergic deregulation of airway smooth muscle contractility.","description":"<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 Ca<sup>2+</sup> 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.","dates":{"release":"2022-01-01T00:00:00Z","publication":"2022 May","modification":"2025-04-19T22:59:26.86Z","creation":"2025-04-19T22:59:26.86Z"},"accession":"S-EPMC9081122","cross_references":{"pubmed":["34800431"],"doi":["10.1016/j.jaci.2021.10.033"]}}