Increased intracellular Cl- concentration promotes ongoing inflammation in airway epithelium

Airway epithelial cells harbor the capacity of active Cl- ransepithelial transport and play critical roles in modulating innate immunity. However, whether intracellular Cl- ccumulation contributes to relentless airway inflammation remains largely unclear. This study showed that, in airway epithelial cells, intracellular Cl- oncentration ([Cl-](i)) was increased after Pseudomonas aeruginosa lipopolysaccharide (LPS) stimulation via nuclear factor-kappa B (NF-kappa B)-phosphodiesterase 4D (PDE4D)-cAMP signaling pathways. Clamping [Cl-](i) at high levels or prolonged treatment with LPS augmented serum-and glucocorticoid-inducible protein kinase 1 (SGK1) phosphorylation and subsequently triggered NF-kappa B activation in airway epithelial cells, whereas inhibition of SGK1 abrogated airway inflammation in vitro and in vivo. Furthermore, Cl--SGK1 signaling pathway was pronouncedly activated in patients with bronchiectasis, a chronic airway inflammatory disease. Conversely, hydrogen sulfide (H2S), a sulfhydryl-containing gasotransmitter, confers anti-inflammatory effects through decreasing [Cl-](i) via activation of cystic fibrosis transmembrane conductance regulator (CFTR). Our study confirms that intracellular Cl- is a crucial mediator of sustained airway inflammation. Medications that abrogate excessively increased intracellular Cl- may offer novel targets for the management of airway inflammatory diseases.