Using Drugs to Probe the Variability of Trans-Epithelial Airway Resistance
Authors
Kendra Tosoni, Diane Cassidy, Barry Kerr, Stephen C. Land, Anil Mehta
Institution
University of Dundee
Country
United Kingdom
Year
2016
Journal
PLOS One
Abstract
Background
Precision medicine aims to combat the variability of the therapeutic response to a given
medicine by delivering the right medicine to the right patient. However, the application of
precision medicine is predicated on a prior quantitation of the variance of the reference
range of normality. Airway pathophysiology provides a good example due to a very variable
first line of defence against airborne assault. Humans differ in their susceptibility to inhaled
pollutants and pathogens in part due to the magnitude of trans-epithelial resistance that
determines the degree of epithelial penetration to the submucosal space. This initial ‘setpoint’
may drive a sentinel event in airway disease pathogenesis. Epithelia differentiated in
vitro from airway biopsies are commonly used to model trans-epithelial resistance but the
‘reference range of normality’ remains problematic. We investigated the range of
electrophysiological characteristics of human airway epithelia grown at air-liquid interface in
vitro from healthy volunteers focusing on the inter- and intra-subject variability both at baseline
and after sequential exposure to drugs modulating ion transport.
Methodology/Principal Findings
Brushed nasal airway epithelial cells were differentiated at air-liquid interface generating
137 pseudostratified ciliated epithelia from 18 donors. A positively-skewed baseline range
exists for trans-epithelial resistance (Min/Max: 309/2963 Ωcm2), trans-epithelial voltage
(-62.3/-1.8 mV) and calculated equivalent current (-125.0/-3.2 μA/cm2; all non-normal,
P<0.001). A minority of healthy humans manifest a dramatic amiloride sensitivity to voltage
and trans-epithelial resistance that is further discriminated by prior modulation of cAMPstimulated
chloride transport.
Conclusions/Significance
Healthy epithelia show log-order differences in their ion transport characteristics, likely
reflective of their initial set-points of basal trans-epithelial resistance and sodium transport.
Our data may guide the choice of the background set point in subjects with airway diseases
and frame the reference range for the future delivery of precision airway medicine.