lium of individuals with CF receiving lung transplantations demonstrates a 
normal voltage (Wood et al . , 1989). 
Primary cultures of airway epithelial cells demonstrate abnormalities in 
Cl - permeability and an inability to secrete more Cl - in response to stimu- 
li that increase intracellular cAMP (Rich et al., 1990) i.e., the epithe- 
lial cells of individuals with CF demonstrate an abnormality in regulation 
of Cl - transport independent of any systemic factors. Consistent with these 
observations, permanent airway epithelial cell lines established from CF 
patients manifests the Cl" channel abnormality (Jetten et al., 1989; Rich 
et al., 1990; Wagner et al. , 1991; Zeitlin et al. , 1991). Single channel 
patch- clamp studies have demonstrated the Cl - abnormality is manifest on 
the apical membrane of airway epithelial cells (Frizzell et al . , 1986; 
Hwang et al . , 1989; Li et al. , 1988; Li et al. , 1989). When the patches 
were attached to the CF cells, the abnormality in Cl" permeability was 
evident. However, when the apical patches' were excised, the Cl - channel 
could be made to function i.e., the CF abnormality is directly expressed in 
airway epithelial cells and appears to involve the regulation of apical Cl - 
channels . 
Finally, in vitro transfer of the normal human CFTR cDNA into airway epi- 
thelial cells from individuals with CF corrects the characteristic abnor- 
mality in Cl - transport (Rich et al. , 1990). 
1.11.2 How Abnormal CFTR Gene Expression Causes the Characteristic Airway 
Disease 
While the link between mutations in the CFTR gene and the respiratory 
abnormalities of cystic fibrosis is definitive, the mechanisms involved in 
the pathogenesis for the airway disease is not. There are two general 
hypotheses, not mutually exclusive, that explain the process: (1) the 
respiratory manifestations result from changes in the electrolyte milieu on 
the surface of the airway epithelium; and (2) the respiratory disease 
results from processes internal to the respiratory epithelial cells. 
Although the exact mechanisms are not defined, an abnormality in electro- 
lyte transport from the apical surface of airway epithelial cells can ex- 
plain all of the pulmonary manifestations of the disease. In this regard, 
transepithelial electrolyte transport likely modulates the quantity and 
composition of respiratory tract epithelial fluid. Thus, an inability to 
actively transport Cl - from the submucosa to the epithelial surface in a 
normal fashion would limit H 2 0 from being secreted from the epithelium in a 
normal fashion. Consequently, the airway secretions would be relatively 
dehydrated, providing a rational scenario for the subsequent development of 
mucus obstruction, infection and inflammation. 
Alternatively, the respiratory disease may result from abnormal expression 
of the CFTR gene modifying processes internal to the respiratory epithelial 
cells. While such mechanisms are presently only hypothetical, they might 
include abnormalities in the pH of intracellular organelles causing dys- 
function of enzymes modifying mucins or abnormal expression of cell compo- 
nents that interact with microorganisms such as Pseudomonas . 
[648] 
Recombinant DNA Research, Volume 16 
