The pH of airway surface liquid (ASL) is a key factor that determines respiratory host defense; ASL acidification impairs and alkalinization enhances key defense mechanisms. Under healthy conditions, airway epithelia secrete base (${\text{HCO}}_3^{-}$) and acid (H⁺) to control ASL pH (pH_ASL). Neutrophil-predominant inflammation is a hallmark of several airway diseases, and TNFα and IL-17 are key drivers. However, how these cytokines perturb pH_ASL regulation is uncertain. In primary cultures of differentiated human airway epithelia, TNFα decreased and IL-17 did not change pH_ASL. However, the combination (TNFα+IL-17) markedly increased pH_ASL by increasing ${\text{HCO}}_3^{-}$ secretion. TNFα+IL-17 increased expression and function of two apical ${\text{HCO}}_3^{-}$ transporters, CFTR anion channels and pendrin Cl⁻/${\text{HCO}}_3^{-}$ exchangers. Both were required for maximal alkalinization. TNFα+IL-17 induced pendrin expression primarily in secretory cells where it was coexpressed with CFTR. Interestingly, significant pendrin expression was not detected in CFTR-rich ionocytes. These results indicate that TNFα+IL-17 stimulate ${\text{HCO}}_3^{-}$ secretion via CFTR and pendrin to alkalinize ASL, which may represent an important defense mechanism in inflamed airways.

中文翻译：

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TNFα和IL-17通过CFTR和pendrin碱化气道表面液体。

气道表面液体（ASL）的pH值是决定呼吸道宿主防御的关键因素；ASL 酸化削弱和碱化增强关键防御机制。在健康条件下，气道上皮细胞分泌碱基（${\text{碳酸氢钠}}_3^{-}$) 和酸 (H ⁺ ) 来控制 ASL pH (pH _ASL )。中性粒细胞为主的炎症是几种气道疾病的标志，而 TNFα 和 IL-17 是关键驱动因素。然而，这些细胞因子如何扰乱 pH _ASL调节尚不确定。在分化的人气道上皮细胞的原代培养物中，TNFα 减少，IL-17 不改变 pH _ASL。然而，组合（TNFα+IL-17）_通过增加${\text{碳酸氢钠}}_3^{-}$分泌。TNFα+IL-17 增加两种顶端的表达和功能${\text{碳酸氢钠}}_3^{-}$转运蛋白、CFTR 阴离子通道和 pendrin Cl ^- /${\text{碳酸氢钠}}_3^{-}$交换器。两者都是最大碱化所必需的。TNFα+IL-17 主要在与 CFTR 共表达的分泌细胞中诱导 pendrin 表达。有趣的是，在富含 CFTR 的离子细胞中未检测到显着的 pendrin 表达。这些结果表明 TNFα+IL-17 刺激${\text{碳酸氢钠}}_3^{-}$通过 CFTR 和 pendrin 分泌以碱化 ASL，这可能是发炎气道的重要防御机制。