Loss of p73 Expression Contributes to Chronic Obstructive Pulmonary Disease

Multiciliated cell (MCC) loss and/or dysfunction is common in the small airways of patients with chronic obstructive pulmonary disease (COPD), but it is unclear if this contributes to COPD lung pathology. To determine if loss of p73 causes a COPD-like phenotype in mice and explore whether smoking or COPD impact p73 expression. p73 mice were crossed with Shh-Cre mice to generate mice lacking MCCs in the airway epithelium. The resulting p73 mice were analyzed using electron microscopy, flow cytometry, morphometry, forced oscillation technique, and single-cell RNA sequencing. Furthermore, the effects of cigarette smoke on p73 transcript and protein expression were examined using and models and in studies including airway epithelium from smokers and patients with COPD. Loss of functional p73 in the respiratory epithelium resulted in a near-complete absence of MCCs in p73 mice. In adulthood, these mice spontaneously developed neutrophilic inflammation and emphysema-like lung remodeling and had progressive loss of secretory cells. Exposure of normal airway epithelium cells to cigarette smoke rapidly and durably suppressed p73 expression and . Furthermore, tumor protein 73 mRNA expression was reduced in the airways of current smokers ( = 82) compared with former smokers ( = 69), and p73-expressing MCCs were reduced in the small airways of patients with COPD ( = 11) compared with control subjects without COPD ( = 12). Loss of functional p73 in murine airway epithelium results in the absence of MCCs and promotes COPD-like lung pathology. In smokers and patients with COPD, loss of p73 may contribute to MCC loss or dysfunction.