Effects of cAMP and CFTR modulation on apical fluid pH in human airway Calu‐3 cells

The airway epithelium serves as the first line of defense against inhaled insults present in the external environment by acting as a physical barrier and through host defense mechanisms. Proper maintenance of these host defense mechanisms relies on the regulation of airway surface liquid (ASL) composition and properties, a process that is tightly controlled by various ion transporters, including the cystic fibrosis transmembrane conductance regulator (CFTR) protein. With evidence suggesting dysfunctional CFTR-mediated bicarbonate secretion leads to airway acidification, resulting in impaired host defenses, there is increased interest in improving ASL pH. The aim of our study was to determine whether pharmacological interventions, via cAMP and CFTR modulators, lead to an increase in pH. Human airway epithelial (Calu-3) cells were exposed to various combinations of cAMP and CFTR modulating agents to assess their effectiveness at elevating apical base secretions (apical fluid) pH. Our results show that pharmacological interventions with cAMP elevating agents and CFTR modulator VX-770 led to significant increases in pH, with combinations leading to greater increases compared to single drug interventions. Our study suggests that cAMP and CFTR modulation has potential as a therapeutic strategy for elevating ASL pH and may be beneficial for respiratory diseases with ASL abnormalities.