Airway epithelial regeneration in lung disease

Understanding normal repair improves our understanding of disease

Lung disease is a major and growing cause of morbidity and mortality globally, affecting approximately 7–8% of the world's population at any time. Diseases of the airways — including asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis, primary ciliary dyskinesia, and rarer genetic conditions — all involve disruption to the airway epithelium, the cellular barrier that lines the respiratory tract and defends it against inhaled injury.

The normal repair response

Unlike the skin or gut, where epithelial turnover is more rapid and regenerative capacity is high, the airway epithelium turns over relatively slowly under normal conditions. However, following epithelial injury — whether from a respiratory virus, inhaled toxicant, or physical trauma — airway basal cells rapidly activate a wound healing programme. Basal cells at the wound edge spread and migrate to cover the denuded area, then proliferate to restore cell density, and finally differentiate to regenerate the mucociliary epithelium. This process is regulated by a network of signalling pathways, including Wnt, Notch, and epidermal growth factor receptor (EGFR) signalling, and involves interactions between epithelial cells and surrounding extracellular matrix and stromal cells.

When regeneration fails: chronic lung disease

In chronic lung diseases, the normal repair programme is disrupted. In COPD, repeated cycles of injury — caused by cigarette smoke and air pollution — lead to structural remodelling of the airway wall, with increased proportions of secretory cells at the expense of ciliated cells (goblet cell metaplasia), impaired mucociliary clearance, and, in severe disease, loss of small airway epithelial integrity. Basal cells from COPD donors demonstrate impaired differentiation capacity in vitro, suggesting a cell-intrinsic contribution to the regenerative deficit.

In asthma, epithelial fragility and aberrant repair contribute to airway remodelling and the cycle of chronic inflammation. In cystic fibrosis, the primary defect is loss of functional CFTR — the chloride channel whose absence disrupts airway surface liquid homeostasis and impairs mucociliary clearance. The resulting mucus plugging and chronic infection cause progressive epithelial damage. Primary ciliary dyskinesia (PCD) is a genetic disorder affecting the structure or function of cilia produced by differentiating basal cells, with the functional consequence of impaired clearance despite an intact regenerative response.

Viral infection and epithelial repair

Respiratory viral infections are among the most common triggers of acute airway epithelial damage. Influenza, respiratory syncytial virus (RSV), and rhinovirus all cause desquamation of the differentiated epithelium, requiring basal cell-mediated repair for recovery. The severity of infection — and the duration of symptoms — is partly a function of how effectively the epithelium is regenerated. Identifying compounds that enhance basal cell-mediated repair represents one avenue towards host-directed antiviral therapeutics — an approach we are actively investigating, including through the development of donor-derived airway ALI models for high-throughput antiviral screening.

Ageing and regenerative decline

The efficiency of airway epithelial regeneration declines with age. Aged basal cells demonstrate reduced proliferative capacity and altered differentiation. Understanding the molecular basis of this decline — and whether it can be reversed or slowed — is relevant both to age-related lung disease and to the design of regenerative therapies for older patients. At EpiCENTR, we are investigating how age-associated changes in basal cell identity and function contribute to impaired regeneration, including the roles of transcription factors such as p63 and structural determinants such as the hemidesmosome complex.

What regenerative medicine might offer

For most chronic lung diseases, the therapeutic goal is currently to slow progression and manage symptoms. No approved therapy has yet demonstrated the ability to reverse established disease. Regenerative approaches — whether through stimulation of endogenous repair pathways, delivery of exogenous stem cells, or gene correction of patient-derived cells — offer a longer-term prospect of restoring functional epithelium rather than simply managing its decline. At EpiCENTR, our work on airway basal cell biology, in vitro airway models, and cell and gene therapy is directed towards making this prospect a reality for children and adults with airway diseases.