Genetic Influences on Airway Remodeling in Asthma

Airway remodeling in asthma describes the structural alterations of the bronchial wall that accompany chronic inflammation, including smooth muscle hypertrophy, subepithelial fibrosis and increased mucous gland mass. Genetic variation plays a central role in determining which individuals develop these persistent changes, with polymorphisms in genes encoding metalloproteases, cytokines and extracellular matrix regulators modulating susceptibility and severity. Key candidate genes—such as ADAM33, ORMDL3 and several members of the serpin family—govern processes of airway epithelial repair, collagen deposition and smooth muscle proliferation. Interactions between genetic predisposition and environmental triggers, including allergens and air pollution, shape the extent and reversibility of remodeling. Understanding these pathways informs the development of precision therapies, from small-molecule inhibitors targeting tyrosine kinase signalling to gene-based interventions aimed at restoring normal tissue architecture. Globally, elucidating heritable determinants of airway structure supports risk stratification, early intervention and the design of novel anti-remodeling agents in both paediatric and adult asthma populations.

Research from Nature Portfolio

Recent studies have exploited a genetically tractable model to show that dysregulation of airway-specific serpins alters branch architecture and impairs oxygenation, linking gene expression changes directly to structural and functional deficits. Overexpression of fly homologues of SCCA1 and SPINK5 induced excessive airway branching and reduced hypoxia tolerance, providing a live demonstration of how serpin variants can drive maladaptive remodelling. Another investigation has introduced a peptide inhibitor of ADAM8 that profoundly attenuates bronchial hyperresponsiveness, tissue remodelling and T helper 2 inflammation in a murine model. By selectively blocking ADAM8 activity, this work highlights the therapeutic promise of targeting cell-surface metalloproteases to prevent or reverse airway wall thickening.

Genetic Influences on Airway Remodeling in Asthma publication trend

The graph below shows the total number of articles in genetic influences on airway remodeling in asthma across all publications each year (not limited to Nature Index journals).

Technical terms

Airway remodelling: Persistent structural changes in bronchial tissue, including smooth muscle growth and subepithelial fibrosis.

Single-nucleotide polymorphism (SNP): A variation at a single DNA base pair position, often influencing gene function or expression.

Serpin: A family of serine protease inhibitors involved in regulating extracellular proteolysis and tissue integrity.

ADAM33: A member of the disintegrin and metalloprotease family implicated in airway smooth muscle proliferation and matrix remodelling.

Bronchial hyperresponsiveness: Exaggerated airway constriction in response to stimuli, reflecting remodelling and inflammation.

References

1. ADAM33′s Role in Asthma Pathogenesis: An Overview. International Journal of Molecular Sciences (2024).
2. Airway specific deregulation of asthma-related serpins impairs tracheal architecture and oxygenation in D. melanogaster. Scientific Reports (2024).
3. Association between ADAM33 Single-Nucleotide Polymorphisms and Treatment Response to Inhaled Corticosteroids and a Long-Acting Beta-Agonist in Asthma. Diagnostics (2023).
4. Triple-tyrosine kinase inhibition by BIBF1000 attenuates airway and pulmonary arterial remodeling following chronic allergen challenges in mice. European Journal of Medical Research (2023).
5. Soluble ADAM33 initiates airway remodeling to promote susceptibility for allergic asthma in early life. JCI Insight (2016).
6. A novel peptide ADAM8 inhibitor attenuates bronchial hyperresponsiveness and Th2 cytokine mediated inflammation of murine asthmatic models. Scientific Reports (2016).