of the 5' flanking region of the CFTR gene has the characteristics of a house- 
keeping-type gene, and the rate of transcription of the CFTR gene in normal 
human bronchial epithelium is only 6% that of the /3-actin gene (51,52). The 
absolute level of CFTR gene expression in airway epithelial cells of indivi- 
duals with CF is not known, but the relative expression of the normal and 
aF 508 allele in heterozygotes is equal (50). Normal expression of the CFTR 
gene may be higher in secretory epithelial cells, particularly in mucus gland 
serous cells of the large airways, Clara cells in the distal bronchi, and in 
type II alveolar epithelial cells. It is not known if this has direct rele- 
vance to the pathogenesis of the disease. In regard to type II cell expres- 
sion, this is a site where there is no clinical disease (except late in the 
course of the disease, where there is a large scale derangement of pulmonary 
architecture) . 
1.8 Pathogenesis of the Respiratory Manifestations of Cystic Fibrosis. Evi- 
dence from a variety of sources strongly argues that the pulmonary manifesta- 
tions of CF result from abnormal expression of the CFTR gene in epithelial 
cells of the tracheobronchial tree. It is not clear, however, how the abnormal 
expression of the CFTR gene product results in the abnormal mucus, coloniza- 
tion with bacteria, and intense and chronic epithelial inflammation in the 
lung that characterize the disease. The available evidence is consistent with 
the concept that it is the inflammation that causes the progressive derange- 
ments to the airways that result in respiratory impairment and eventual death 
from respiratory failure. There is overwhelming evidence that respiratory 
manifestations of CF are linked to mutations for the CFTR gene in both paren- 
tal alleles (1) . Measurements of the transepithelial voltage of the tracheo- 
bronchial tree (lumen voltage relative to the submucosa) of CF patients reveal 
a higher voltage than that observed in normals, or in individuals with other 
diseases of the tracheobronchial tree, consistent with the concept that there 
is a local abnormality in electrolyte transport (53) . In vivo evaluation of 
the airway epithelium of individuals with CF receiving lung transplantations 
demonstrates a normal voltage (54). Primary cultures of airway epithelial 
cells demonstrate abnormalities in Cl' permeability and an inability to se- 
crete more Cl" in response to stimuli that increase intracellular cAMP (23) 
i.e., the epithelial 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 manifest the Cl' channel abnormality (23,55-57). Single chan- 
nel patch-clamp studies have demonstrated the Cl' abnormality is manifest on 
the apical membrane of airway epithelial cells (24-27). 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 epitheli- 
al cells and appears to involve the regulation of apical Cl' channels. Final- 
ly, in vitro transfer of the normal human CFTR cDNA into airway epithelial 
cells from individuals with CF corrects the characteristic abnormality in Cl' 
transport (23) . 
While the link between mutations in the CFTR gene and the respiratory abnorm- 
alities 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. First, the respiratory mani- 
festations may result from changes in the electrolyte milieu on the surface of 
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