Epithelial cells in chronic obstructive pulmonary disease exacerbations: Targets for lung repair

Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease characterized by chronic respiratory symptoms and persistent, often progressive, loss of lung function. Patients, particularly those with severe disease, frequently experience exacerbations triggered by viral and bacterial infections. Exacerbations are closely linked to the rapid decline in lung function, accounting for more than 50% of the accelerated loss over the lifetime of a patient with COPD. Airway epithelial cells play a central role in the development of COPD exacerbations. As the first line of defense, these cells form tight intercellular junctions, creating a protective barrier against pathogens and producing mucus and antimicrobial peptides to eliminate bacteria and viruses. Upon pathogen recognition via pattern recognition receptors, epithelial cells initiate inflammatory responses by releasing cytokines and chemokines that recruit immune cells. This inflammation can become dysregulated in COPD, contributing to tissue damage and exacerbation severity. Furthermore, airway epithelial cells are particularly important in promoting lung repair and restoring homeostasis. They modulate inflammation resolution, promote extracellular matrix remodeling, and support lung regeneration. In COPD, chronic inflammation and repeated exacerbations impair epithelial function, disrupt repair mechanisms, and hinder lung regeneration, contributing to irreversible damage. This review highlights the crucial role of airway epithelial cells in COPD exacerbations, focusing on their regulatory functions in maintaining barrier integrity, managing inflammation and promoting epithelial lung repair. Moreover, current and future therapeutic strategies aimed at enhancing epithelial barrier function, controlling airway inflammation, and supporting lung recovery and regeneration are discussed, highlighting key directions for future investigation. SIGNIFICANCE STATEMENT: Chronic obstructive pulmonary disease exacerbations represent a pharmacologically actionable period characterized by epithelial barrier disruption, dysregulated inflammation, and impaired repair. This review positions airway epithelial cells as central orchestrators of these processes, regulating host defense, immune interactions, and regenerative responses. By targeting epithelial dysfunction during exacerbations, this review highlights the potential therapies that go beyond symptom relief and support lung repair and modify disease progression.