Influenza virus infection alters ion channel function of airway and alveolar cells: mechanisms and physiological sequelae

Abstract

The cystic fibrosis transmembrane conductance regulator (CFTR) and the amiloride-sensitive epithelial sodium channels (ENaC) are located in the apical membranes of airway and alveolar epithelial cells. These transporters play an important role in the regulation of lung fluid balance across airway and alveolar epithelia by being the conduits for chloride (Cl) and bicarbonate ([Formula: see text]) secretion and sodium (Na) ion absorption, respectively. The functional role of these channels in the respiratory tract is to maintain the optimum volume and ionic composition of the bronchial periciliary fluid (PCL) and alveolar lining fluid (ALF) layers. The PCL is required for proper mucociliary clearance of pathogens and debris, and the ALF is necessary for surfactant homeostasis and optimum gas exchange. Dysregulation of ion transport may lead to mucus accumulation, bacterial infections, inflammation, pulmonary edema, and compromised respiratory function. Influenza (or flu) in mammals is caused by influenza A and B viruses. Symptoms include dry cough, sore throat, and is often followed by secondary bacterial infections, accumulation of fluid in the alveolar spaces and acute lung injury. The underlying mechanisms of flu symptoms are not fully understood. This review summarizes our present knowledge of how influenza virus infections alter airway and alveolar epithelial cell CFTR and ENaC function in vivo and in vitro and the role of these changes in influenza pathogenesis.

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

“…Taken altogether, these data demonstrate that in vivo IAV infection reduces Na + absorption (through ENaC) and Cl -/HCO 3 secretion (through CFTR) across mouse nasal epithelium transiently and consistently. This phenotype resembles that seen in patients with CF and COPD (13), which are known to be associated with altered airway rheology and mucociliary defects (14,15).…”

“…Maintenance of the pulmonary mucosal barrier and gas exchange unit are critically dependent on intricate regulation of Na + absorption and Cland HCO 3 secretion via the ENaC and CFTR channels, respectively (reviewed in ref. 13). Previous studies have identified ENaC and CFTR channel dysfunction in response to IAV in various in vitro cell culture systems (24,25,35).…”

Susceptibility of influenza viruses to hypothiocyanite and hypoiodite produced by lactoperoxidase in a cell-free system

“…Bronchial epithelial cells (BEC) are a primary target for influenza virus replication [ 6 ]. Early response by BECs to influenza virus is crucial in determining progression of viral infection, adaptive immunity, and lung pathogenesis [ 7 ].…”

Influenza Virus in Community-Acquired Pneumonia: Current Understanding and Knowledge Gaps

“…Influenza virus infection may induce cell death in pneumocytes and damage the tight junctions, leading to fluid flooding into the alveolar space. 17,50,51 Also, the inhibition of epithelial ion channels (cystic fibrosis transmembrane conductance regulator and the amiloride-sensitive epithelial sodium channels) by influenza virus also accounts for the delayed alveolar fluid clearance 52,53 (►Fig. 1B, C).…”