FASEB J：新发现为囊性纤维化和慢阻肺病人治疗带来希望

近日，来自北卡罗来纳大学的研究者揭示了一种新的策略，或许在某一天可以帮助囊性纤维化病人（cystic fibrosis，CF）以及慢阻肺障碍（COPD）病人更好地延长其生命。相关研究成果刊登在了近日的国际杂志FASEB Journal上。

研究者揭示了SPLUNC1蛋白和其衍生物肽可以通过影响上皮细胞钠通道（ENaC）来帮助病人似的病人的厚的粘膜变薄。研究者Robert Tarran表示，我们希望这项研究可以为开发出基于肽的抑制剂来使得病人机体的粘膜脱水，从而使得病人的病情得到缓解，研究者还表示，这将会提高机体的厚粘膜的清除率，并且提高肺部功能以清除更多的致病菌。

为了研究具体是SPLUNC1蛋白的哪一部分影响ENaC，研究者消除了该蛋白质的各个部分使其失去功能。研究结果显示，消除SPLUNC1蛋白85%以后，该蛋白质的剩余部分仍可以影响ENaC，这也就解释了影响ENaC的结构域部分在蛋白质15%的那部分。随后研究者合成了15%结构域的氨基酸肽，并且检测了其结合ENaC的能力以及在人类支气管上皮细胞（基于囊性纤维化病人）抑制液体吸收的能力。研究结果显示，这种肽类可以抑制ENaC和液体吸收的能力，但是不影响其离子通道的结构。研究者还发现ENaC在囊性纤维化病人的气管中可以被影响超过24小时，表明这种肽类对于治疗过度活跃的ENaC的囊性纤维化病人有潜在的治疗效果。

健康的人们往往想当然地认为呼吸是理所应当的，可是对于CF和COPD病人来说每天和呼吸做着抗争，因为其肺部厚厚的粘膜严重影响着他们的呼吸。这项研究为临床治疗CF和COPD病人提供了新的见解。

编译自：New Proteins to Clear the Airways in Cystic Fibrosis and COPD

doi:10.1096/fj.12-207431fj.12-207431
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Identification of SPLUNC1's ENaC-inhibitory domain yields novel strategies to treat sodium hyperabsorption in cystic fibrosis airways

Carey A. Hobbs*, Maxime G. Blanchard§, Stephan Kellenberger§, Sompop Bencharit†, Rui Cao*, Mehmet Kesimer*, William G. Walton‡, Matthew R. Redinbo‡, M. Jackson Stutts* and Robert Tarran*,1

The epithelial sodium channel (ENaC) is responsible for Na+ and fluid absorption across colon, kidney, and airway epithelia. We have previously identified SPLUNC1 as an autocrine inhibitor of ENaC. We have now located the ENaC inhibitory domain of SPLUNC1 to SPLUNC1's N terminus, and a peptide corresponding to this domain, G22-A39, inhibited ENaC activity to a similar degree as full-length SPLUNC1 (∼2.5 fold). However, G22-A39 had no effect on the structurally related acid-sensing ion channels, indicating specificity for ENaC. G22-A39 preferentially bound to the β-ENaC subunit in a glycosylation-dependent manner. ENaC hyperactivity is contributory to cystic fibrosis (CF) lung disease. Addition of G22-A39 to CF human bronchial epithelial cultures (HBECs) resulted in an increase in airway surface liquid height from 4.2 ± 0.6 to 7.9 ± 0.6 μm, comparable to heights seen in normal HBECs, even in the presence of neutrophil elastase. Our data also indicate that the ENaC inhibitory domain of SPLUNC1 may be cleaved away from the main molecule by neutrophil elastase, which suggests that it may still be active during inflammation or neutrophilia. Furthermore, the robust inhibition of ENaC by the G22-A39 peptide suggests that this peptide may be suitable for treating CF lung disease.—Hobbs, C. A., Blanchard, M. G., Kellenberger, S., Bencharit, S., Cao, R., Kesimer, M., Walton, W. G., Redinbo, M. R., Stutts, M. J., Tarran, R. Identification of SPLUNC1's ENaC-inhibitory domain yields novel strategies to treat sodium hyperabsorption in cystic fibrosis airways.