The airway epithelium: an orchestrator of inflammation, a key structural barrier and a therapeutic target in severe asthma

Abstract

Asthma is a disease of heterogeneous pathology, typically characterised by excessive inflammatory and bronchoconstrictor responses to the environment. The clinical expression of the disease is a consequence of the interaction between environmental factors and host factors over time, including genetic susceptibility, immune dysregulation and airway remodelling. As a critical interface between the host and the environment, the airway epithelium plays an important role in maintaining homeostasis in the face of environmental challenges. Disruption of epithelial integrity is a key factor contributing to multiple processes underlying asthma pathology. In this review, we first discuss the unmet need in asthma management and provide an overview of the structure and function of the airway epithelium. We then focus on key pathophysiological changes that occur in the airway epithelium, including epithelial barrier disruption, immune hyperreactivity, remodelling, mucus hypersecretion and mucus plugging, highlighting how these processes manifest clinically and how they might be targeted by current and novel therapeutics.

FIGURE 1

The airway epithelium in healthy individuals and patients with asthma. In the healthy airway, ciliated epithelial cells are connected by tight junctions, forming a physical barrier against infiltration by environmental agents. Goblet cells secrete mucus, which traps pathogens and transports them out of the airways through mucociliary clearance. In asthma, a combination of environmental insults and patient factors leads to epithelial barrier disruption. Epithelial damage stimulates the release of epithelial cytokines (thymic stromal lymphopoietin (TSLP), interleukin (IL)-25 and IL-33), which act on epithelial, subepithelial and immune cell types to drive multiple pathophysiological changes underlying the development, persistence and exacerbation of asthma. These changes include mucus hypersecretion and plugging, impaired viral resistance, airway remodelling, immune hyperreactivity, airway smooth muscle (ASM) hypertrophy and airway hyperresponsiveness. ECM: extracellular matrix; EMT: epithelial-to-mesenchymal transition; IFN: interferon; T2: type 2; TGF: transforming growth factor; VEGF: vascular endothelial growth factor.

FIGURE 2

The role of the epithelium in driving clinical manifestations of asthma. Disruption of the airway epithelium triggers the release of epithelial cytokines. Either directly or through downstream inflammatory cascades, epithelial cytokines drive pathophysiological changes to the airways that result in clinical manifestations of asthma, including wheezing, dyspnoea, cough, exacerbations and reversible or permanent loss of lung function. ASM: airway smooth muscle; BEC: blood eosinophil count; F_ENO: fractional exhaled nitric oxide; FEV₁: forced expiratory volume in 1 s; IFN: interferon; IL: interleukin; T2: type 2; TSLP: thymic stromal lymphopoietin.