Loss of p73 Expression Contributes to Chronic Obstructive Pulmonary Disease

慢性阻塞性肺病 呼吸上皮 医学 气道 病理 上皮 体内 炎症 呼吸系统 呼吸道疾病 免疫学 内科学 生物 麻醉 生物技术
作者
Bradley W. Richmond,Clayton B. Marshall,Jessica B. Blackburn,T.S. Tufenkjian,Brian D. Lehmann,Wei Han,Dawn C. Newcomb,Sergey Gutor,Raphael P. Hunt,Danielle L. Michell,Kasey C. Vickers,Vasiliy V. Polosukhin,Timothy S. Blackwell,Jennifer A. Pietenpol
出处
期刊:American Journal of Respiratory and Critical Care Medicine [American Thoracic Society]
卷期号:209 (2): 153-163 被引量:2
标识
DOI:10.1164/rccm.202303-0503oc
摘要

Rationale: Multiciliated cell (MCC) loss/dysfunction is common in the small airways of patients with COPD but it is unclear if this contributes to COPD lung pathology. Objectives: To determine if loss of p73 causes a COPD-like phenotype in mice and explore whether smoking or COPD impact p73 expression. Methods: p73floxE7-E9 mice were crossed with Shh-Cre mice to generate mice lacking MCCs in the airway epithelium. The resulting p73Δairway mice were analyzed using electron microscopy, flow cytometry, morphometry, forced oscillation technique, and single-cell RNA sequencing. Further, the effects of cigarette smoke on p73 transcript and protein expression were examined using in vitro and in vivo models and in studies including airway epithelium from smokers and COPD patients. Measurements and Main Results: Loss of functional p73 in the respiratory epithelium resulted in a near-complete absence of MCCs in p73Δairway 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 in vitro and in vivo. Further, TP73 mRNA expression was reduced in the airways of current smokers (n=82) compared to former smokers (n=69) and p73-expressing MCCs were reduced in the small airways of COPD patients (n=11) compared to non-COPD controls (n=12). Conclusions: 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.
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