Losartan ameliorates TGF-β1-induced CFTR dysfunction and improves correction by cystic fibrosis modulator therapies.
Losartan ameliorates TGF-β1-induced CFTR dysfunction and improves correction by cystic fibrosis modulator therapies.
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DOI：
10.1172/jci155241
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发表时间：
2022-06-01
影响因子：
15.9
通讯作者：
Salathe, Matthias
中科院分区：
文献类型：
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作者：
Kim, Michael D.;Bengtson, Charles D.;Yoshida, Makoto;Niloy, Asef J.;Dennis, John S.;Baumlin, Nathalie;Salathe, Matthias
高效的调节剂治疗显著改善囊性纤维化（CF）患者的预后。elexacaftor，tezacaftor和ivacaftor（ETI）的三重组合使许多但不是所有CF跨膜传导调节因子（CFTR）中最常见的F508 del突变的人受益。在这里，我们发现，在开始ETI后，汗液氯化物浓度反应差和肺功能改善与上气道活性TGF-β1水平升高相关。此外，TGF-β1损害了ETI校正的F508 del-CFTR的功能，从而增加了气道表面液体（ASL）吸收率，并诱导体外原代CF支气管上皮细胞中粘液高浓度。TGF-β1不仅降低CFTR mRNA表达，而且还与TNF-α、TNF-α蛋白和TNF-α、TNF-α和COX-2 mRNA表达的增加有关。洛沙坦改善了TGF-β1介导的对ETI校正的F508 del-CFTR功能的抑制，并降低了TNFA和COX 2 mRNA以及TNF-α蛋白的表达。这可能是通过改善突变CFTR的校正而不是增加其mRNA（对增强无影响），从而逆转TGF-β1的负面作用并改善体外CF气道上皮中ASL的水合作用而发生的。重要的是，这些作用独立于1型血管紧张素II受体抑制。
Highly effective modulator therapies dramatically improve the prognosis for those with cystic fibrosis (CF). The triple combination of elexacaftor, tezacaftor, and ivacaftor (ETI) benefits many, but not all, of those with the most common F508del mutation in the CF transmembrane conductance regulator (CFTR). Here, we showed that poor sweat chloride concentration responses and lung function improvements upon initiation of ETI were associated with elevated levels of active TGF-β1 in the upper airway. Furthermore, TGF-β1 impaired the function of ETI-corrected F508del-CFTR, thereby increasing airway surface liquid (ASL) absorption rates and inducing mucus hyperconcentration in primary CF bronchial epithelial cells in vitro. TGF-β1 not only decreased CFTR mRNA, but was also associated with increases in the mRNA expression of TNFA and COX2 and TNF-α protein. Losartan improved TGF-β1–mediated inhibition of ETI-corrected F508del-CFTR function and reduced TNFA and COX2 mRNA and TNF-α protein expression. This likely occurred by improving correction of mutant CFTR rather than increasing its mRNA (without an effect on potentiation), thereby reversing the negative effects of TGF-β1 and improving ASL hydration in the CF airway epithelium in vitro. Importantly, these effects were independent of type 1 angiotensin II receptor inhibition.