title: Using Drugs to Probe the Variability of Trans-Epithelial Airway Resistance.
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 'set-point' 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.
  
  
  RESULTS
  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 Ω·cm2), 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 cAMP-stimulated chloride transport.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Cardiovascular and Diabetes Medicine, University of Dundee, Medical Research Institute Ninewells Hospital and Medical School, Dundee, Scotland, United Kingdom.
authors.forename: Kendra
authors.initials: K
authors.lastname: Tosoni
authors.affiliation: Division of Cardiovascular and Diabetes Medicine, University of Dundee, Medical Research Institute Ninewells Hospital and Medical School, Dundee, Scotland, United Kingdom.
authors.forename: Diane
authors.initials: D
authors.lastname: Cassidy
authors.affiliation: School of Medicine, University of Dundee, Dundee, Scotland, United Kingdom.
authors.forename: Barry
authors.initials: B
authors.lastname: Kerr
authors.affiliation: Division of Cardiovascular and Diabetes Medicine, University of Dundee, Medical Research Institute Ninewells Hospital and Medical School, Dundee, Scotland, United Kingdom.
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Land
authors.affiliation: Division of Cardiovascular and Diabetes Medicine, University of Dundee, Medical Research Institute Ninewells Hospital and Medical School, Dundee, Scotland, United Kingdom.
authors.forename: Anil
authors.initials: A
authors.lastname: Mehta
mesh_terms: D000293:Adolescent; D000328:Adult; D000403:Airway Resistance / Q000187:drug effects*; D000584:Amiloride / Q000494:pharmacology*; D017097:Electric Impedance; D055724:Electrophysiological Phenomena; D004847:Epithelial Cells / Q000187:drug effects; D005260:Female; D006801:Humans; D017136:Ion Transport / Q000187:drug effects; D008297:Male; D009297:Nasal Mucosa / Q000187:drug effects / Q000502:physiology*; D013223:Statistics as Topic; D055815:Young Adult
chemical_list: D000584:Amiloride