Daniel P Cook, Michael V Rector, Drake C Bouzek, Andrew S Michalski, Nicholas D Gansemer, Leah R Reznikov, Xiaopeng Li, Mallory R Stroik, Lynda S Ostedgaard, Mahmoud H Abou Alaiwa, Michael A Thompson, Y S Prakash, Ramaswamy Krishnan, David K Meyerholz, Chun Y Seow, David A Stoltz

An asthma-like airway phenotype has been described in people with cystic fibrosis (CF). Whether these findings are directly due to loss of cystic fibrosis transmembrane conductance regulator (CFTR) function or secondary to chronic airway infection and/or inflammation has been difficult to determine. Airway contractility is primarily determined by airway smooth muscle. We tested the hypothesis that CFTR is expressed in airway smooth muscle and directly affects airway smooth muscle contractility. Newborn pigs, both wild-type and with CF (before the onset of airway infection and inflammation), were used in this study. High-resolution immunofluorescence was used to identify the subcellular localization of CFTR in airway smooth muscle. Airway smooth muscle function was determined with tissue myography, intracellular calcium measurements, and regulatory myosin light chain phosphorylation status. Precision cut lung slices were used to investigate the therapeutic potential of CFTR modulation on airway reactivity. We found that CFTR localizes to the sarcoplasmic reticulum compartment of airway smooth muscle and regulates airway smooth muscle tone. Loss of CFTR function led to delayed calcium reuptake following cholinergic stimulation and increased myosin light chain phosphorylation. CFTR potentiation with ivacaftor decreased airway reactivity in precision cut lung slices following cholinergic stimulation. Loss of CFTR alters porcine airway smooth muscle function and may contribute to the airflow obstruction phenotype observed in human CF. Airway smooth muscle CFTR may represent a therapeutic target in CF and other diseases of airway narrowing.