NEW YORK (Reuters Health) - Mice engineered to overexpress epithelial sodium channels (ENaC) in their airways develop a cystic fibrosis (CF)-like lung disease that may provide a model for studying the pathogenesis and treatment of CF, according to a report in the April 18th advance online publication of Nature Medicine.
Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene are responsible for the development of cystic fibrosis in humans, the authors point out, but mice deficient in CFTR do not develop spontaneous pulmonary disease.
“It has been unclear how CFTR, which acts as a chloride channel and regulator of the sodium channel, causes lung disease,” Dr. Marcus Mall from The University of North Carolina at Chapel Hill, told Reuters Health. “In particular, the relative importance of these two functions has been controversial and difficult to test. This model demonstrated for the first time that the accelerated sodium transport alone is sufficient to cause this disease.”
Dr. Mall and colleagues hypothesized that accelerated sodium absorption, by lowering airway surface liquid (ASL) volume and impairing mucus clearance of the airways, could play a key role in the pathogenesis of CF. They tested their hypothesis by generating mice whose airway-specific overexpression of ENaC would be expected to increase sodium absorption in the lower airways.
Indeed, overexpression of the Scnn1b subunit of ENaC resulted in sodium hyperabsorption in mouse airways, the authors report, and this led to airway surface volume depletion and abnormal mucus transport.
Bronchoalveolar lavage analysis confirmed the presence of neutrophilic airway inflammation in the absence of bacterial infection, while other experiments confirmed the impaired clearance of Haemophilus influenzae and Pseudomonas aeruginosa instilled into the airways.
“The model demonstrates that airway surface dehydration is critical in initiating CF lung disease,” Dr. Mall concluded. “We will therefore focus on the development and testing of drugs that act on this root cause and improve airway surface hydration, either by blocking the sodium channels or by increasing the secretion of salt and water.”
Source: Nature Medicine 2004.doi:10.1038/nm1028. [ Google search on this article ]
MeSH Headings:Animal Diseases: Animals, Laboratory: Animals, Transgenic: Disease Models, Animal: Invertebrates: Mice, Transgenic: Organisms, Transgenic: DiseasesCopyright © 2002 Reuters Limited. All rights reserved. Republication or redistribution of Reuters content, including by framing or similar means, is expressly prohibited without the prior written consent of Reuters. Reuters shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. Reuters and the Reuters sphere logo are registered trademarks and trademarks of the Reuters group of companies around the world.
