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Updated: Jun 6, 2025
Assessment of Respiratory Function in Conscious Mice by Double-chamber Plethysmography
Published on: July 10, 2018
N-cadherin antagonism is bronchoprotective in severe asthma models
Nicolas L Pereira1, Niccole Schaible2, Abhishek Desai1
1Lung and Vascular Inflammation Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Abstract:
Severe asthma induces substantial mortality and chronic disability due to intractable airway obstruction, which may become resistant to currently available therapies including corticosteroids and β-adrenergic agonist bronchodilators. A key effector of these changes is exaggerated airway smooth muscle (ASM) cell contraction to spasmogens. No drugs in clinical use effectively prevent ASM hyperresponsiveness in asthma across all severities. We find that N-cadherin, a membrane cell-cell adhesion protein up-regulated in ASM from patients with severe asthma, is required for the development of airway obstruction induced by allergic airway inflammation in mice. Inhibition of N-cadherin by ADH-1 reduced airway hyperresponsiveness independent of allergic inflammation, prevented bronchoconstriction, and actively promoted bronchodilation of airways ex vivo. ADH-1 inhibited ASM contraction by disrupting N-cadherin-δ-catenin interactions, which decreased intracellular actin remodeling. These data provide evidence for an intercellular communication pathway mediating ASM contraction and identify N-cadherin as a potential therapeutic target for inhibiting bronchoconstriction in asthma.
Insights
N-cadherin, a protein found in airway smooth muscle cells, drives severe asthma symptoms. Inhibiting N-cadherin with ADH-1 offers a potential new therapy to reduce airway constriction and improve asthma treatment.
Area of Science:
- Pulmonary Medicine
- Cell Biology
- Pharmacology
Background:
- Severe asthma is characterized by intractable airway obstruction and disability.
- Current therapies for severe asthma, including corticosteroids and bronchodilators, are often ineffective.
- Exaggerated airway smooth muscle (ASM) contraction to spasmogens is a key factor in asthma pathology.
Purpose of the Study:
- To investigate the role of N-cadherin in severe asthma.
- To evaluate ADH-1 as a potential therapeutic agent for inhibiting ASM hyperresponsiveness and bronchoconstriction.
Main Methods:
- Examined N-cadherin expression in ASM from severe asthma patients.
- Utilized a mouse model of allergic airway inflammation to assess airway obstruction.
- Administered ADH-1 to inhibit N-cadherin and evaluated its effects on airway hyperresponsiveness, bronchoconstriction, and bronchodilation ex vivo.
Main Results:
- N-cadherin is upregulated in ASM from severe asthma patients and is required for airway obstruction in a mouse model.
- ADH-1 treatment reduced airway hyperresponsiveness independently of allergic inflammation.
- ADH-1 prevented bronchoconstriction and promoted bronchodilation ex vivo by disrupting N-cadherin-δ-catenin interactions and decreasing actin remodeling.
Conclusions:
- N-cadherin plays a critical role in mediating ASM contraction and airway obstruction in severe asthma.
- N-cadherin represents a promising therapeutic target for developing novel treatments to inhibit bronchoconstriction in asthma.
- ADH-1 demonstrates potential as a drug to manage severe asthma by targeting N-cadherin.
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