The epithelial era of asthma research: knowledge gaps and future direction for patient care

Abstract

The Epithelial Science Expert Group convened on 18-19 October 2023, in Naples, Italy, to discuss the current understanding of the fundamental role of the airway epithelium in asthma and other respiratory diseases and to explore the future direction of patient care. This review summarises the key concepts and research questions that were raised. As an introduction to the epithelial era of research, the evolution of asthma management throughout the ages was discussed and the role of the epithelium as an immune-functioning organ was elucidated. The role of the bronchial epithelial cells in lower airway diseases beyond severe asthma was considered, as well as the role of the epithelium in upper airway diseases such as chronic rhinosinusitis. The biology and application of biomarkers in patient care was also discussed. The Epithelial Science Expert Group also explored future research needs by identifying the current knowledge and research gaps in asthma management and ranking them by priority. It was identified that there is a need to define and support early assessment of asthma to characterise patients at high risk of severe asthma. Furthermore, a better understanding of asthma progression is required. The development of new treatments and diagnostic tests as well as the identification of new biomarkers will also be required to address the current unmet needs. Finally, an increased understanding of epithelial dysfunction will determine if we can alter disease progression and achieve clinical remission.

FIGURE 1

Asthma management through the ages. The time frames noted in this overview are approximate date ranges for each era. ^#: The epithelial era is based on a current theoretical era of ongoing scientific research focused on the epithelium.

FIGURE 2

The role of the epithelium in upper and lower airway diseases. The airway epithelium consists largely of three main cell types, namely ciliated cells, secretory (goblet and club) cells and basal cells. Ciliated and secretory cells facilitate clearance of mucus and debris from the upper and lower airways. The upper airways comprise approximately 20% of goblet cells which secrete mucins and other glycoproteins that contribute to mucus viscosity. In the lower airways, there is an increased presence of club cells, which are implicated in epithelial repair and facilitate homeostasis. Similar inflammatory processes (classified as T1, T2 and T3 responses) are associated with both upper and lower airway diseases, in which interaction with external triggers results in the release of cytokines and inflammatory mediators. Structural changes to the airway, termed airway remodelling, may also occur. IFN: interferon; IgE: immunoglobulin E; IL: interleukin; ILC: innate lymphoid cell; Th: T-helper; TNF: tumour necrosis factor; TSLP: thymic stromal lymphopoietin.

FIGURE 3

Mucus plugging in healthy and asthmatic airways. When particles enter a healthy airway, they are captured in secreted mucus and expelled by the action of ciliated cells in a process known as mucociliary clearance. When particles enter an asthmatic airway, ineffective mucus clearance occurs and particles remain trapped. Several immune factors that correlate with ineffective mucus clearance have been identified: Th2 cells produce IL-13, which contributes to upregulation of MUC5AC, and IL-4 and IL-5, which contribute to eosinophil recruitment. Eosinophils and neutrophils release extracellular traps to clear pathogens, which increase airway mucus viscosity. Eosinophils are associated with Charcot–Leyden crystal protein formation, which induces mucus secretion. Eosinophils also increase the stimulation of MUC5AC. The formation of mucus plugs that occlude the airway has a number of clinical implications including cough, bronchoconstriction, oedema, decreased ventilation and obstruction of the airway. IL: interleukin; Th: T-helper.

FIGURE 4

Knowledge gaps in the epithelial era of respiratory science prioritised by research needs. Key knowledge gaps were prioritised in terms of feasibility of implementation and impact of the research. Numbers 1–10 represent the order of prioritisation of research needs.