A73-11 Club Cell-specific HuR Deletion Reduces Airway Epithelial Dapk1 Expression and Promotes Airway Cell Proliferation and Airflow Obstruction in Mice

Abstract Airflow obstruction is a major contributor to the morbidity and mortality of chronic obstructive pulmonary disease (COPD), yet the mechanisms by which cigarette smoke drives airway dysfunction remain incompletely understood. Using lung tissue and primary human airway epithelial cells from healthy and COPD subjects, we observed reduced expression of the RNA-binding protein HuR in the airway epithelium of COPD patients. HuR is a broadly expressed post-transcriptional regulator that controls mRNA stability and translation. To investigate how HuR depletion contributes to airway pathology, we generated Club cell-specific HuR knockout mice and exposed them to cigarette smoke for six months. Compared with smoke-exposed littermates, these mice exhibited greater airway epithelial proliferation and airflow obstruction. Single-cell transcriptomic analysis revealed that these changes were accompanied by reduced Dapk1 expression in Club and ciliated epithelial cells. Consistently, silencing HuR in primary human airway epithelial cells abrogated the smoke-induced upregulation of DAPK1. Since DAPK1 has previously been shown to limit epithelial proliferation and protect against cigarette smoke-induced emphysema, these findings suggest that smoke-mediated HuR depletion disrupts DAPK1 expression, leading to dysregulated epithelial repair and the development of airflow obstruction in COPD. This abstract is funded by: NIH