In the final stages of the disease, autopsy studies demonstrate small 
airways become completely obstructed with secretions. There are bronchiec- 
tatic cysts occupying as much as 50X of the cross-sectional area of the 
lung (Boat et al . , 1989) and the bronchioles are stenosed and obliterated. 
Bronchiectasis with marked derangements of the epithelial surface and the 
bronchial wall is common. 
1.10 CFTR Gene Expression in the Airway Epithelium 
The CFTR gene is expressed in the epithelium of the human nose, trachea and 
bronchi (Trapnell et al . , 1991a). On the surface epithelium, expression is 
very low, averaging 1-2 mRNA transcripts per cell (Trapnell et al . , 1991a). 
Consistent with this observation, the sequence of the 5' flanking region of 
the CFTR gene has the characteristics of a housekeeping- type gene, and the 
rate of transcription of the CFTR gene in normal human bronchial epithelium 
is only 6% that of the /?-actin gene (Chou et al . , 1991; Yoshimura et al., 
1991b). The absolute level of CFTR gene expression in airway epithelial 
cells of individuals with CF is not known, but the relative rate of expres- 
sion of the normal and aF508 allele in a heterozygote is equal (Trapnell et 
al., 1991a). Recent studies suggest normal expression of the CFTR gene may 
be higher in secretory epithelial cells, particularly serous cells in mucus 
glands of the large airways ( J . Wilson, personal communication). It is not 
known if this has direct relevance to the pathogenesis of the disease. In 
mice, there is also expression in the alveolar epithelial cells ( J . 
Whitsett, personal communication), a site where there is no clinical dis- 
ease (except late in the course of the disease, where there is a large 
scale derangement of pulmonary architecture) . 
1.11 Pathogenesis of the Respiratory Manifestations of Cystic Fibrosis 
Evidence from a variety of sources strongly argue that the pulmonary mani- 
festations of CF result from abnormal expression of the CFTR gene in epi- 
thelial cells for the tracheobronchial tree (Figure 1.11-A). It is not 
clear, however, how the abnormal expression of the CFTR gene product re- 
sults in the abnormal mucus, colonization with bacteria and intense, and 
chronic epithelial inflammation in the lung that characterize the disease. 
All available evidence is consistent with the concept that it is the in- 
flammation that causes the progressive derangements to the airways that 
result in respiratory impairment and eventual death from respiratory fail- 
ure. 
1.11.1 CFTR Mutations and Respiratory Disease 
In regards to the link of mutations of the CFTR gene to airway disease, 
there is overwhelming evidence that respiratory manifestations of CF are 
linked to mutations for the CFTR gene in both parental alleles (Boat et 
al . , 1989). Further, measurements of the transepithelial voltage of the 
tracheobronchial 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 
(Knowles et al . , 1981). Finally, in vivo evaluation for the airway epithe- 
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Recombinant DNA Research, Volume 16 
