Loss of p73 Expression Contributes to Chronic Obstructive Pulmonary Disease.

Abstract

<b>Rationale:</b> 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. <b>Objectives:</b> To determine if loss of p73 causes a COPD-like phenotype in mice and explore whether smoking or COPD impact p73 expression. <b>Methods:</b> p73^floxE7-E9 mice were crossed with Shh-Cre mice to generate mice lacking MCCs in the airway epithelium. The resulting p73^Δairway 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 <i>in vitro</i> and <i>in vivo</i> models and in studies including airway epithelium from smokers and patients with COPD. <b>Measurements and Main Results:</b> Loss of functional p73 in the respiratory epithelium resulted in a near-complete absence of MCCs in p73^Δairway 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 <i>in vitro</i> and <i>in vivo</i>. Furthermore, tumor protein 73 mRNA expression was reduced in the airways of current smokers (<i>n</i> = 82) compared with former smokers (<i>n</i> = 69), and p73-expressing MCCs were reduced in the small airways of patients with COPD (<i>n</i> = 11) compared with control subjects without COPD (<i>n</i> = 12). <b>Conclusions:</b> 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.