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Influenza-mediated reduction of lung epithelial ion channel activity leads to dysregulated pulmonary fluid homeostasis
Jeffrey D. Brand, … , Sadis Matalon, Kevin S. Harrod
Jeffrey D. Brand, … , Sadis Matalon, Kevin S. Harrod
Published October 18, 2018
Citation Information: JCI Insight. 2018;3(20):e123467. https://doi.org/10.1172/jci.insight.123467.
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Research Article Pulmonology Virology

Influenza-mediated reduction of lung epithelial ion channel activity leads to dysregulated pulmonary fluid homeostasis

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Abstract

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.

Authors

Jeffrey D. Brand, Ahmed Lazrak, John E. Trombley, Ren-Jay Shei, A. Timothy Adewale, Jennifer L. Tipper, Zhihong Yu, Amit R. Ashtekar, Steven M. Rowe, Sadis Matalon, Kevin S. Harrod

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Figure 8

IAV decreases specific subunits of ENaC, CFTR, and Na/K-ATPase at the cell surface.

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IAV decreases specific subunits of ENaC, CFTR, and Na/K-ATPase at the ce...
NHBEs were grown at an air-liquid interface and infected with A/California/07/2009 at a MOI of 3. (A) ENaC, CFTR, and Na/K-ATPase protein abundance was measured by Western blotting. For ENaC and CFTR measurements, biotinylated apical membrane proteins were immunoblotted with specific antibodies against ENaC subunits and CFTR, respectively. Blots are representative of 3 separate experiments. (B) Densitometry demonstrates reductions in ENaC subunits, CFTR, and α-Na/K-ATPase subunit, but no difference was observed in the expression of the regulatory β subunit Na/K-ATPase levels. Data were analyzed by 1-way ANOVA and post hoc Tukey test for multiple comparisons. N = 3 per group. *P < 0.001 compared with mock-infected controls.

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