Airway epithelial cells harbor the capacity of active Cl^- transepithelial transport and play critical roles in modulating innate immunity. However, whether intracellular Cl^- accumulation contributes to relentless airway inflammation remains largely unclear. This study showed that, in airway epithelial cells, intracellular Cl^- concentration ([Cl^-]_i) was increased after Pseudomonas aeruginosa lipopolysaccharide (LPS) stimulation via nuclear factor-κB (NF-κB)-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-κB 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.

中文翻译：

---

增加的细胞内 Cl- 浓度会促进气道上皮细胞持续发炎。

气道上皮细胞具有主动 Cl ^-跨上皮转运的能力，并在调节先天免疫方面发挥关键作用。然而，细胞内 Cl ^-积累是否会导致持续的气道炎症仍不清楚。本研究表明，在气道上皮细胞中，通过核因子-κB (NF-κB)-磷酸二酯酶 4D (PDE4D)-cAMP 信号通路刺激铜绿假单胞菌脂多糖 (LPS) 后，细胞内 Cl ^-浓度 ([Cl ^- ] _i ) 增加路径。钳位 [Cl ^- ] _i高水平或长期使用 LPS 增强血清和糖皮质激素诱导蛋白激酶 1 (SGK1) 磷酸化，随后触发气道上皮细胞中的 NF-κB 激活，而抑制 SGK1 可在体外和体内消除气道炎症。此外，Cl ^- -SGK1 信号通路在支气管扩张症（一种慢性气道炎症性疾病）患者中显着激活。相反，硫化氢 (H ₂ S) 是一种含巯基的气体递质，它通过激活囊性纤维化跨膜传导调节剂 (CFTR)来降低 [Cl ^- ] _i，从而发挥抗炎作用。我们的研究证实细胞内 Cl ^-是持续气道炎症的重要介质。消除过度增加的细胞内 Cl ^-的药物可能为气道炎症性疾病的管理提供新的目标。