Airway Inflammation Mechanisms in Asthma Pathophysiology

Asthma is a chronic respiratory disorder marked by episodic airway obstruction, inflammation and remodelling. Central to its pathophysiology is an interplay between airway epithelial cells, resident structural cells and infiltrating immune cells. In the classic type 2 phenotype, allergens breach a compromised epithelial barrier and activate dendritic cells, leading to differentiation of type 2 helper T cells (Th2) and group 2 innate lymphoid cells (ILC2). These cells secrete interleukins (IL-4, IL-5, IL-13) that drive eosinophil recruitment, mucus hypersecretion and smooth muscle contraction. In a subset of patients, a neutrophilic pattern emerges, orchestrated by Th17 cells, ILC3 and innate sensors, resulting in steroid resistance and persistent inflammation. Cytokine and chemokine networks promote oxidative stress, protease release and extracellular matrix deposition. Over time, chronic inflammation induces structural alterations—epithelial–mesenchymal transition, subepithelial fibrosis and smooth muscle hypertrophy—collectively termed airway remodelling, which underpins fixed airflow limitation and declining lung function.

Research from Nature Portfolio

Recent seminal work has elucidated the role of high mobility group box 1 (HMGB1) in driving epithelial–mesenchymal transition in human airway epithelial cells. This study demonstrated that HMGB1 engagement of its receptor for advanced glycation end products initiates the PI3K/AKT/GSK3β/β-catenin axis, leading to downregulation of epithelial markers E-cadherin and ZO-1 and upregulation of mesenchymal markers such as vimentin. Inhibition of this pathway reversed the phenotypic shift, indicating a direct mechanistic link between alarmin signalling and airway remodelling processes. The findings position HMGB1 and its downstream signalling intermediates as attractive targets to prevent fibrosis and loss of lung function in chronic asthma.

Airway Inflammation Mechanisms in Asthma Pathophysiology publication trend

The graph below shows the total number of articles in airway inflammation mechanisms in asthma pathophysiology across all publications each year (not limited to Nature Index journals).

Technical terms

Airway hyperresponsiveness (AHR): increased sensitivity of the bronchial airways to various stimuli, leading to excessive constriction and airflow obstruction.

Epithelial–mesenchymal transition (EMT): process by which epithelial cells lose polarity and adhesion to acquire mesenchymal features, contributing to tissue remodelling and fibrosis.

Type 2 helper T cells (Th2 cells): subset of CD4+ T lymphocytes that produce interleukins such as IL-4, IL-5 and IL-13, central to allergic airway inflammation and eosinophil recruitment.

Innate lymphoid cells type 3 (ILC3s): innate immune cells that secrete IL-17 and IL-22, implicated in neutrophilic inflammation and mucosal defence.

Stimulator of interferon genes (STING): cytosolic receptor that detects double-stranded DNA and activates downstream inflammatory signalling pathways.

PANoptosis: a composite inflammatory cell death pathway integrating features of pyroptosis, apoptosis and necroptosis.

Extracellular vesicles (EVs): lipid-bound particles released by cells that transport proteins, lipids and nucleic acids to mediate intercellular communication.

Receptor for advanced glycation end products (RAGE): cell-surface receptor for damage-associated molecular patterns such as HMGB1, triggering pro-inflammatory signalling.

References

1. The Burden of Pediatric Asthma. Frontiers in Pediatrics (2018).
2. High mobility group box 1-induced epithelial mesenchymal transition in human airway epithelial cells. Scientific Reports (2016).
3. Micrococcus luteus-derived extracellular vesicles attenuate neutrophilic asthma by regulating miRNAs in airway epithelial cells. Experimental & Molecular Medicine (2023).
4. STING‐dependent induction of neutrophilic asthma exacerbation in response to house dust mite. Allergy (2024).