REGIONAL EXPRESSION OF CFTR IN DEVELOPING HUMAN RESPIRATORY TISSUES

Morbidity and mortality in cystic fibrosis (CF) patients is strongly r elated to their respiratory disease. We have analyzed, by means of in situ hybridization, the localization and levels of CFTR mRNA in fetal, newborn, and infant respiratory tissues. Measurable levels of CFTR tr anscript are present in the fetal primordial epithelium of the pseudog landular stage lung. During the following stages of lung development, CFTR expression decreases in cells of the future alveolar spaces and i s gradually limited to the epithelium of the small airways. After birt h, expression decreases in the small airways and is not detected in al veolar epithelia. In trachea and large bronchi, a differential pattern of expression is also observed. No CFTR expression is found in fetal submucosal glands during fetal development, but appears gradually in t he newborn period. Since CFTR codes for a secretory Cl- channel, these data probably reflect the changes that occur in the lung transition f rom a fluid-secreting to an absorbing organ. The pattern of expression seems paradoxical in view of the clinical-pathological manifestations of CF. Although CFTR is expressed in the normal fetus and lung develo pment is influenced by the amount of fetal lung liquid, newborns affec ted with CF have normal lungs. In addition, the earliest pathologic ch ange described in CF lungs is hyperplasia of the submucosal glands, ye t expression in these structures is seen only after birth. An improved understanding of the factors that alter the expected relationship bet ween CFTR expression and pathologic lesions in the fetal lung may prov ide important insights into the pathogenesis and potential treatment o f lung disease in CF patients.