CD38 Plays an Age-related Role in Cholinergic Deregulation of Airway Smooth Muscle Contractility

Overview

Journal J Allergy Clin Immunol

Specialty Allergy & Immunology

Date 2021 Nov 20

PMID 34800431

Citations 2

Authors

Yan Bai

Alonso G P Guedes

Ramaswamy Krishnan

Xingbin Ai

Affiliations

Soon will be listed here.

Abstract

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 Ca 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.

Citing Articles

Precision cut lung slices: an integrated ex vivo model for studying lung physiology, pharmacology, disease pathogenesis and drug discovery.

Koziol-White C, Gebski E, Cao G, Panettieri Jr R Respir Res. 2024; 25(1):231.

PMID: 38824592 PMC: 11144351. DOI: 10.1186/s12931-024-02855-6.

Utilizing the Precision-Cut Lung Slice to Study the Contractile Regulation of Airway and Intrapulmonary Arterial Smooth Muscle.

Bai Y, Ai X J Vis Exp. 2022; (183).

PMID: 35604150 PMC: 11147671. DOI: 10.3791/63932.

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