Quantitative analysis of ion transport in human airway epithelial cells

• Main Author: O'Donoghue, D. L.
• Published: University College London (University of London) 2014
• Subjects: 616.3
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.631960

In the human airways, transepithelial ion transport is facilitated by a complex arrangement of ion channel, pump, cotransporter and tight junction proteins. The transepithelial potential difference (Vt), which shows characteristic changes in cystic fibrosis (CF) disease, is commonly measured in the study of epithelial ion transport. In this thesis I develop a mathematical model of ion transport in human nasal epithelia (HNE), in order to quantitatively investigate the relationship between individual transport protein activities and the transepithelial potential generated. In the first part of this work, I investigate the biophysical basis of hyperpolarised basal Vt and increased amiloride sensitive Vt in CF HNE cells. Using published electrophysiological measurements from in vitro experiments, I estimate the value of apical Na+ and apical Cl- permeability in both CF and non-CF HNE cells. I find apical Na+ permeability is increased in CF relative to non-CF cells, and apical Cl- permeability is decreased in CF, suggesting increased epithelial sodium channel (ENaC) activity, as well as decreased activity of anion specific CFTR channels, is responsible for the abnormal bioelectric properties of CF HNE cells. In the second part of this work, I focus on the nasal potential difference (NPD) test commonly made in patients with CF, investigating the biophysical basis of interpatient variability in NPD measurements. I find that the variation in amiloride insensitive Vt observed in a group of CF patients, cannot be accounted for by variation in apical Na+ and Cl- permeability alone. It is necessary to assume incomplete block of ENaC channels by amiloride, and patient to patient variability in other physiological parameters, in order to fully explain the observed variability in this cohort of NPD traces.