Regulation of Ion Channel Physiology in Airway Epithelial cells in response to Influenza A Virus Infection
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Epithelial cells lining the upper airways are characterized by low sodium absorption and elevated chloride secretion. Together, the movement of these ions creates the osmotic drive to hydrate the airways. Recent studies indicate that influenza is capable of directly modulating the vectorial transport of sodium and chloride ions. However, the direct impact of influenza has not been studied with respect to potassium channels. This is significant because potassium conductance creates the driving force for chloride secretion. Disruptions to this process leads to edema formation in the lungs and can subsequently cause Acute Respiratory Distress Syndrome. Additionally, it has been demonstrated that the induction of pro-inflammatory cytokines in infected cells may contribute to altered ion channel function, further exacerbating edema formation. The purpose of this study was to assess the direct and indirect effects of influenza virus infection on potassium and chloride ion channel function in a secretory epithelial cell model. In order to assess the direct effects we exposed polarized epithelial cell monolayers to varying doses of H1N1 virus. Potassium and chloride channel function was measured by means of short-circuit current in an Ussing chamber. The immune response to viral infection was determined by RT-qPCR and Bioplex suspension array. Virus conditioned media (CM), and IL-8 were used to characterize the indirect effects on non-infected cells. We observed an increase in chloride secretion, consistent with edema formation, when 60% of the epithelium was infected, and after CM treatment. This observation correlated with increased potassium channel conductance through the calcium-activated (KCNN4) and cAMP-activated potassium channels (KCNQ1), which was ameliorated upon specific inhibition of these channels. The data suggest that the mixture of pro-inflammatory cytokines induced by viral infection directly up-regulate these potassium channels. However, treatment with IL-8 also appears to increase chloride secretion, although the underlying mechanism remains to be determined, as it is not mediated through KCNN4 and KCNQ1. We conclude that the strong induction of cytokines in infected cells act in a paracrine manner on non-infected cells to increase potassium channel conductance. This up-regulation of potassium channels subsequently drives an increase in chloride secretion, leading to fluid build-up in the lungs and edema formation.
DegreeMaster of Science (M.Sc.)
DepartmentVeterinary Biomedical Sciences
ProgramVeterinary Biomedical Sciences
CommitteeMisra, Vikram; Blakley, Barry; Wobeser, Bruce
Copyright DateAugust 2013