Title: Influenza-mediated reduction of lung epithelial ion channel activity leads to dysregulated pulmonary fluid homeostasis.
Authors: Brand, Jeffrey D; Lazrak, Ahmed; Trombley, John E; Shei, Ren-Jay; Adewale, A Timothy; Tipper, Jennifer L; Yu, Zhihong; Ashtekar, Amit R; Rowe, Steven M; Matalon, Sadis; Harrod, Kevin S
Published In JCI Insight, (2018 10 18)
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.
PubMed ID: 30333319
MeSH Terms: Aminopyridines/pharmacology; Animals; Benzodioxoles/pharmacology; Bronchi/metabolism; Bronchi/pathology; Bronchi/virology; Cells, Cultured; Cystic Fibrosis Transmembrane Conductance Regulator/metabolism*; Disease Models, Animal; Dogs; Epithelial Cells; Epithelial Sodium Channels/metabolism*; Female; Humans; Influenza A virus/pathogenicity*; Influenza, Human/complications; Influenza, Human/pathology*; Influenza, Human/virology; Madin Darby Canine Kidney Cells; Male; Mice; Primary Cell Culture; Pulmonary Edema/pathology; Pulmonary Edema/virology; Respiratory Distress Syndrome, Adult/pathology; Respiratory Distress Syndrome, Adult/virology; Respiratory Mucosa/metabolism; Respiratory Mucosa/pathology*; Respiratory Mucosa/virology; Sodium-Potassium-Exchanging ATPase/metabolism; Water-Electrolyte Balance/drug effects