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in Human Bronchial Epithelia
1 Laboratory of Pulmonary Pathobiology, National Institute of Environmental Health Sciences, Res. Triangle Park, NC, USA
2 Cystic Fibrosis/Pulmonary Research and Treatment Center, University of North Carolina, Chapel Hill, NC, USA
3 The Wellcome Trust Center for Cell-Matrix Research, University of Manchester, Manchester, United Kingdom
4 Department of Thoracic/Head and Neck Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, USA
* To whom correspondence should be addressed. E-mail: grayt{at}niehs.nih.gov.
Mucociliary transport in the airways significantly depends on the liquid and mucin components of the airway surface liquid (ASL). The regulation of ASL water and mucin content during pathological conditions is not well understood.
We hypothesized that airway epithelial mucin production and liquid transport are regulated in response to inflammatory stimuli and tested this hypothesis by investigating the effects of the pleiotropic, early-response cytokine, IL-1
, on cultured primary human bronchial epithelial (HBE) and second passage, normal human tracheobronchial epithelial (NHTBE) cell cultures. Fully differentiated NHTBE cultures secreted two major airway mucins, MUC5AC and MUC5B. IL-1, in a dose and time dependent manner, increased the secretion of MUC5AC, but not MUC5B. MUC5AC mRNA levels were only transiently increased at one and four hours after the start of IL-1 treatment and returned to control levels thereafter even though MUC5AC mucin production remained elevated for at least 72 hrs. Synchronous with elevated MUC5AC secretion, ASL volume increased, its % solid was reduced, and the pH/[HCO3-] of the ASL was elevated. ASL volume changes reflected altered ion transport, including an up regulation of Cl- secretory currents (via CFTR and Ca+ + activated Cl- conductance) and an inhibition of ENaC-mediated absorptive Na+ currents. IL-1 increased CFTR mRNA levels without affecting those for ENaC sub-units. The synchronous regulation of ASL mucin and liquid metabolism triggered by IL-1 may be an important defense mechanism of the airway epithelium to enhance mucociliary clearance during airway inflammation.
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