Cystic Fibrosis Airway Mucus Hyperconcentration Produces a Vicious Cycle of Mucin, Pathogen, and Inflammatory Interactions that Promote Disease Persistence.

The dynamics describing the vicious cycle characteristic of CF lung disease, initiated by stagnant mucus and perpetuated by infection and inflammation, remain unclear. Here we determine the effect of the CF airway milieu, with persistent muco-obstruction, resident pathogens, and inflammation, on the mucin quantity/quality that govern lung disease pathogenesis/progression. The concentrations of MUC5AC and MUC5B, were measured and characterized in sputum samples from CF (N=44) and healthy (N=29) subjects with respect to their macromolecular properties, degree of proteolysis, and glycomics diversity. These parameters were related to quantitative microbiome and clinical data. MUC5AC, and MUC5B concentrations were elevated, 30- and 8-fold respectively, in CF as compared to control sputum. Mucin parameters did not correlate with hypertonic saline, inhaled corticosteroids or antibiotics use. No differences in mucin parameters were detected at baseline vs during exacerbations. Mucin concentrations significantly correlated with the age and sputum human neutrophil elastase (HNE) activity. Although significantly more proteolytic cleavages were detected in CF mucins, their macromolecular properties, e.g., size and molecular weight, were not significantly different than controls likely reflecting the role of S-S bonds in maintaining multimeric structures. No evidence of giant mucin macromolecule reflecting oxidative stress-induced cross-linking was found. Mucin glycomic analysis revealed significantly more sialylated glycans in CF and the total abundance of non-sulfated O-glycans was correlated with the relative abundance of pathogens. Collectively, the interaction of mucins, pathogens, epithelium, and inflammatory cells promotes proteomic and glycomic changes that reflects a persistent muco-obstructive, infectious, and inflammatory state.