Recent advances in cystic fibrosis


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Abstract

The discovery of the cystic fibrosis gene and the identification of the cystic fibrosis transmembrane regulator protein product have advanced our understanding of the consequences of the gene defect on the structure, function, and intracellular processing of the transmembrane regulator protein. Over 100 mutations causing cystic fibrosis have been identified, and their effect on cystic fibrosis transmembrane regulator function has elucidated the role of specific protein segments. Evidence indicates that cystic fibrosis transmembrane regulator constitutes the actual chloride channel and that mutations cause defective intracellular processing in this regulator, with reduced numbers and activity of the chloride channel. The pH of intracellular organelles is also altered, resulting in secondary abnormalities in cystic fibrosis mucoproteins. Clinical management, however, has remained substantially unaltered. Genetic screening for carriers is problematic because of the large numbers of mutations. Serum immunoreactive trypsinogen is used for neonatal screening, although the cost-effectiveness of these programs is still under debate. Pharmacologic manipulation of the chloride channel and gene replacement therapy have been successful in laboratory preparations but have not been tried in either animal or human models. Interpatient transmission of bacteria has been confirmed, justifying patient segregation programs. The mode or transmission and host susceptibility factors have not been characterized. Anti-inflammatory agents may suppress the host reaction to chronic endobronchial infection. Clinical trials of these agents, however, have not been completed. Finally, despite improved surgical techniques, lung transplantation remains an option for only a limited number of patients.

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