CFTR I556V Variant Exacerbates Cigarette Smoke-Induced Airway Inflammation in COPD by Promoting NLRP3 Inflammasome Activation

Background and Objective: Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene are known to cause cystic fibrosis (CF), a condition that shares several pathophysiological pulmonary features with chronic obstructive pulmonary disease (COPD). Despite these similarities, the relationship between CFTR gene mutations and the risk of developing COPD remains unclear and poorly understood.

Methods

We employed exon sequencing to detect CFTR exon variations in 208 COPD patients and 100 control subjects with normal lung function. Subsequently, we applied the adenine base editor system to generate cells and animal models carrying the CFTR chr7:117227874A>G (I556V) variant. Airway epithelial cell models were used to examine the effect of the I556V variant on reactive oxygen species (ROS) levels and mitochondrial membrane potential. Additionally, conventional I556V-CFTR variant ( CFTRV/V ) and wild-type ( CFTRI/I ) mice were exposed to either air or 6 months of cigarette smoke. Immune cell counts were obtained from bronchoalveolar lavage fluid (BALF) samples.