EXPRESSION OF THE CYSTIC-FIBROSIS GENE IN ADULT HUMAN LUNG

Critical to an understanding of the pulmonary disease in cystic fibros is (CF) and the development of effective gene therapies is a definitio n of the distribution and regulation of CF gene expression in adult hu man lung. Previous studies have detected the product of the CF gene, t he CF transmembrane conductance regulator (CFTR), in submucosal glands of human bronchi. In this report, we have characterized the distribut ion of CFTR RNA and protein in the distal airway and alveoli of human lungs. Samples from eight human lungs were analyzed for CFTR expressio n by in situ hybridization and immunocytochemistry. CFTR was detected in a subpopulation of epithelial cells at every level of the distal lu ng, including proximal, terminal, and respiratory bronchioles, and the alveoli. However, there was substantial variation in the level of CFT R expression between samples. In bronchioles, CFTR protein localized t o the apical plasma membrane and was found primarily in a subpopulatio n of nonciliated cells. CFTR was expressed in the same distribution as the Clara cell marker CC10 in proximal bronchioles, however, expressi on was discordant in the more distal bronchioles and alveoli where CC1 0 was not detected. These studies suggest that epithelial cells of the distal lung may play a primary role in the pathogenesis of CF as well as expand the spectrum of target cells that should be considered in t he development of gene therapies.