Influenza-mediated reduction of lung epithelial ion channel activity leads to dysregulated pulmonary fluid homeostasis
Influenza-mediated reduction of lung epithelial ion channel activity leads to dysregulated pulmonary fluid homeostasis
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DOI：
10.1172/jci.insight.123467
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发表时间：
2018-10-18
期刊：
影响因子：
8
通讯作者：
Harrod, Kevin S.
中科院分区：
文献类型：
--
作者：
Brand, Jeffrey D.;Lazrak, Ahmed;Harrod, Kevin S.
严重流感（IAV）感染可发展为支气管肺炎和水肿，导致获得性呼吸窘迫综合征（ARDS）和病理生理。肺水肿和异常液体调节的根本原因在很大程度上仍然未知，特别是关于病毒介导机制的作用。通过测量鼻电位差和单细胞电生理，我们发现不同的IAV菌株在体内降低了小鼠呼吸和肺泡上皮上皮钠通道（ENaC）和囊性纤维化跨膜调节剂（CFTR）的功能。离子通道活性的降低明显局限于体内病毒感染的细胞，而不是旁观者未感染的肺上皮。多种证据表明ENaC和CFTR在急性感染期间功能紊乱；然而，只有CFTR功能障碍持续超过感染期。在病毒感染的人气道上皮细胞中，ENaC、CFTR、Na、k - atp酶活性和蛋白水平也降低。ENaC和CFTR的降低导致人气管支气管培养物和iav感染小鼠气道表面液体形态的改变。药理学校正CFTR功能可改善iav诱导的生理变化。这些变化与粘液淤积和肺水肿一致；此外，他们表明，重新调整治疗干预纠正CFTR功能障碍可能对治疗IAV肺病理生理有效。
Severe influenza (IAV) infection can develop into bronchopneumonia and edema, leading to acquired respiratory distress syndrome (ARDS) and pathophysiology. Underlying causes for pulmonary edema and aberrant fluid regulation largely remain unknown, particularly regarding the role of viral-mediated mechanisms. Herein, we show that distinct IAV strains reduced the functions of the epithelial sodium channel (ENaC) and the cystic fibrosis transmembrane regulator (CFTR) in murine respiratory and alveolar epithelia in vivo, as assessed by measurements of nasal potential differences and single-cell electrophysiology. Reduced ion channel activity was distinctly limited to virally infected cells in vivo and not bystander uninfected lung epithelium. Multiple lines of evidence indicated ENaC and CFTR dysfunction during the acute infection period; however, only CFTR dysfunction persisted beyond the infection period. ENaC, CFTR, and Na, K-ATPase activities and protein levels were also reduced in virally infected human airway epithelial cells. Reduced ENaC and CFTR led to changes in airway surface liquid morphology of human tracheobronchial cultures and airways of IAV-infected mice. Pharmacologic correction of CFTR function ameliorated IAV-induced physiologic changes. These changes are consistent with mucous stasis and pulmonary edema; furthermore, they indicate that repurposing therapeutic interventions correcting CFTR dysfunction may be efficacious for treatment of IAV lung pathophysiology.