of this proposal (57). In brief, it was found that the transepithelial electric potential 
difference in vivo of patients with CF was routinely 2 1/2 fold higher than that of 
normal or disease control patients. A large series of studies of CF lung resulted 
from the development of this technology. First, it was found that on a population 
basis the raised nasal PD discriminated very accurately between patients with CF 
and those with other lung diseases (17). At present, it appears that this technique 
discriminates better than the sweat Cl" test in a wide variety of patients. Second, 
through the use of specific ion transport inhibitors and ion substitution protocols, 
the major defects in electrolyte transport in the superficial airway epithelium 
consequent to mutations in the CFTR gene were uncovered (58). In brief, the 
protocols that applied amiloride and substitution of Na + ions on the luminal 
surface of the nasal cavity revealed the evidence for accelerated Na + transport. 
Similarly, the bioelectric responses to luminal Cl" substitution and the failure to 
respond with the bioelectric correlate of Cl" secretion to superfused (3-agonists in 
the nasal cavity revealed the first evidence for the airway epithelial Cl" secretory 
defect in CF. Finally, the technique is presently being used to explore 
genotype/phenotype interactions, focussing on the importance of defects in ion 
transport as the mechanistic link between these two levels of disease description. 
Studies of the nasal epithelium have provided a major impetus for the 
development of novel drugs targeted at rectifying the ion transport defects of CF. 
The first of the drugs targeted at abnormal electrolyte transport, the Na + channel 
blocker amiloride, was first identified as a potentially important therapeutic agent in 
a series of in vivo studies of nasal epithelium in normal subjects and CF patients 
(17). The initial observations were made with amiloride superfused on the 
superficial nasal epithelium in vivo. These data were confirmed and extended in 
studies that defined amiloride’s actions as an inhibitor of excessive Na + absorption 
in freshly excised CF nasal mucosa in vitro (15). Based on these leads from the nasal 
cavity, subsequent studies in animals showed that amiloride conserved water on 
airway surfaces and increased the hydration of secretions, and that these actions 
were without safety concerns (59-61). Finally, these studies led to a clinical trial of 
amiloride for the treatment of CF lung disease, which, in preliminary studies, 
appears to be promising (27). 
A similar paradigm has been followed for the investigation of novel 
therapeutic agents targeted on the plasma membrane Cl" secretory defect. In brief, 
studies with nasal epithelium, both in vivo and in vitro, identified the profound 
actions of extracellular triphosphate nucleotides on inducing Cl" secretion in CF 
patients as well as normal subjects (28,62,63). Again, these studies have led to a 
subsequent long series of studies focussing on the efficacy of these compounds in the 
lung and safety issues. Preliminary studies investigating these issues in CF patients 
are currently underway. 
The nasal epithelium has also been used for studies of the response of 
mucosal surfaces to potentially toxic substances. The response of the nasal surface 
to potentially pathogenic viruses, e.g., rhinoviruses, has been investigated in a series 
of studies designed to determine the site of rhinoviral replication and the 
inflammatory and immunological responses mounted to this virus (64). These types 
of studies typically involve inhalation of virus followed by repetitive lavages of nasal 
Recombinant DNA Research, Volume 17 
[447] 
