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Regulation of MUC5AC mucin secretion and airway surface liquid metabolism by IL-1 in human bronchial epithelia

¹Laboratory of Pulmonary Pathobiology, National Institute of Environmental Health Sciences, Research Triangle Park 27709; ²Cystic Fibrosis/Pulmonary Research and Treatment Center, University of North Carolina, Chapel Hill, North Carolina 27599-7248; ⁴Department of Thoracic/Head & Neck Medical Oncology, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030; and ³Wellcome Trust Centre for Cell-Matrix Research, University of Manchester, Manchester M13 9PT, United Kingdom

Submitted 19 December 2002 ; accepted in final form 26 September 2003

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 and second-passage, normal human tracheo-bronchial 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 1 and 4 h after the start of IL-1 treatment and returned to control levels thereafter, even though MUC5AC mucin production remained elevated for at least 72 h. Synchronous with elevated MUC5AC secretion, ASL volume increased, its percentage of solid was reduced, and the pH/[] of the ASL was elevated. ASL volume changes reflected altered ion transport, including an upregulation of Cl^- secretory currents (via CFTR and Ca²⁺-activated Cl^- conductance) and an inhibition of epithelial sodium channel (ENaC)-mediated absorptive Na⁺ currents. IL-1 increased CFTR mRNA levels without affecting those for ENaC subunits. 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.

normal human tracheobronchial epithelial; air-liquid interface; cystic fibrosis transmembrane conductance regulator

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