MUC5B Overproduction Disrupts Club Cell Mediated Alveolar Repair in COPD

Chronic obstructive pulmonary disease (COPD) is characterized by small airway disease (SAD) and emphysema, but mechanisms linking these pathologies remain unclear. SAD arises early and is the primary site of airflow limitation, marked by epithelial injury, mucus obstruction, and bronchiole loss. Excessive production of the mucin MUC5B by bronchiolar club cells is a key feature of SAD and is associated with impaired mucociliary clearance and inflammation. Club cells also function as progenitors for alveolar type II (ATII) cells, yet how their regenerative capacity is altered in COPD is unknown.

To determine whether MUC5B overproduction in small airway club cells alters their capacity to regenerate ATII cells and contributes to emphysema progression.

We assessed MUC5B expression in human emphysematous lungs and a porcine pancreatic elastase (PPE)-induced mouse model of emphysema. Genetic approaches were used to overexpress or conditionally delete Muc5b in club cells to evaluate effects on club-to-ATII differentiation, alveolar structure, and lung function in health and emphysema.

MUC5B is overexpressed in small airway club cells in human emphysematous lungs and animal models. Muc5b overexpression impairs differentiation of club cells into ATII cells and worsened lung function decline in emphysema. Importantly, conditional deletion of Muc5b during early disease stages restored club cell-derived alveolar regeneration.

MUC5B overproduction links SAD to defective alveolar repair by limiting club cell progenitor function. Targeting MUC5B may restore epithelial regeneration and slow early COPD progression.