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Cystic fibrosis (CF) lung disease is characterized by early and persistent mucus accumulation and neutrophilic inflammation in the distal airways. Identification of the factors in CF mucopurulent secretions that perpetuate CF mucoinflammation may provide strategies for novel CF pharmacotherapies. We show that IL-1[beta], with IL-1[alpha], dominated the mucin prosecretory activities of supernatants of airway mucopurulent secretions (SAMS). Like SAMS, IL- 1[beta] alone induced MUC5B and MUC5AC protein secretion and mucus hyperconcentration in CF human bronchial epithelial (HBE) cells. Mechanistically, IL-1[beta] induced the sterile a motif-pointed domain containing ETS transcription factor (SPDEF) and downstream endoplasmic reticulum to nucleus signaling 2 (ERN2) to upregulate mucin gene expression. Increased mRNA levels of IL1B, SPDEF, and ERN2 were associated with increased MUC5B and MUC5ACexpression in the distal airways of excised CF lungs. Administration of an IL-1 receptor antagonist (IL- 1Ra) blocked SAMS-induced expression of mucins and proinflammatory mediators in CF HBE cells. In conclusion, IL-1[alpha] and IL-1[beta] are upstream components of a signaling pathway, including IL-1R1 and downstream SPDEF and ERN2, that generate a positive feedback cycle capable of producing persistent mucus hyperconcentration and IL-1[alpha] and/or IL- 1[beta]-mediated neutrophilic inflammation in the absence of infection in CF airways. Targeting this pathway therapeutically may ameliorate mucus obstruction and inflammation-induced structural damage in young CF children., Introduction Beginning soon after birth, cystic fibrosis (CF) lung disease is characterized by a heterogeneous, persistent mucoinflammatory environment. Abnormal airway epithelial ion transport predisposes the CF neonatal/childhood lung to mucoinflammatory [...]

Airway epithelia are confronted with distinct signals emanating from the luminal and/or serosal environments. This study tested whether airway epithelia exhibit polarized intracellular free calcium [MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII] and anion secretory responses to 5' triphosphate nucleotides (ATP/UTP), which may be released across both barriers of these epithelia. In both normal and cystic fibrosis (CF) airway epithelia, mucosal exposure to ATP/UTP increased [MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII] and anion secretion, but both responses were greater in magnitude for CF epithelia. In CF epithelia, the mucosal nucleotide-induced response was mediated exclusively via [MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII] interacting with a [Ca.sup.2+]-activated [Cl.sup.-] channel (CaCC). In normal airway epithelia (but not CF), nucleotides stimulated a component of anion secretion via a chelerythrine-sensitive, [Ca.sup.2+]-independent PKC activation of cystic fibrosis transmembrane conductance regulator. In normal and CF airway epithelia, serosally applied ATP or UTP were equally effective in mobilizing [MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII]. However, serosally applied nucleotides failed to induce anion transport in CF epithelia, whereas a PKC-regulated anion secretory response was detected in normal airway epithelia. We conclude that (1) in normal nasal epithelium, apical/basolateral purinergic receptor activation by ATP/UTP regulates separate [Ca.sup.2+]-sensitive and [Ca.sup.2+]-insensitive (PKC-mediated) anion conductances; (2) in CF airway epithelia, the mucosal ATP/UTP-dependent anion secretory response is mediated exclusively via [MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII]; and (3) [MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII] regulation of the [Ca.sup.2+]-sensitive anion conductance (via CaCC) is compartmentalized in both CF and normal airway epithelia, with basolaterally released [MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII] failing to activate CaCC in both epithelia. KEY WORDS: cystic fibrosis transmembrane conductance regulator * purinergic receptors * triphosphate nucleotides * protein kinase C * anion secretion