1. A glycopolymer improves vascoelasticity and mucociliary transport of abnormal cystic fibrosis mucus.
- Author
-
Fernandez-Petty CM, Hughes GW, Bowers HL, Watson JD, Rosen BH, Townsend SM, Santos C, Ridley CE, Chu KK, Birket SE, Li Y, Leung HM, Mazur M, Garcia BA, Evans TIA, Libby EF, Hathorne H, Hanes J, Tearney GJ, Clancy JP, Engelhardt JF, Swords WE, Thornton DJ, Wiesmann WP, Baker SM, and Rowe SM
- Subjects
- Animals, Cystic Fibrosis genetics, Cystic Fibrosis pathology, Cystic Fibrosis Transmembrane Conductance Regulator genetics, Disease Models, Animal, Ferrets, Glucosamine pharmacology, Glucosamine therapeutic use, Humans, Mice, Mice, Inbred CFTR, Mucin-5B chemistry, Mucus metabolism, Polymers therapeutic use, Protein Structure, Quaternary drug effects, Rats, Respiratory Mucosa drug effects, Respiratory Mucosa pathology, Viscosity drug effects, Cystic Fibrosis drug therapy, Glucosamine analogs & derivatives, Mucin-5B metabolism, Mucociliary Clearance drug effects, Mucus drug effects, Polymers pharmacology
- Abstract
Cystic fibrosis (CF) is characterized by increased mucus viscosity and delayed mucociliary clearance that contributes to progressive decline of lung function. Mucus in the respiratory and GI tract is excessively adhesive in the presence of airway dehydration and excess extracellular Ca2+ upon mucin release, promoting hyperviscous, densely packed mucins characteristic of CF. Therapies that target mucins directly through ionic interactions remain unexploited. Here we show that poly (acetyl, arginyl) glucosamine (PAAG), a polycationic biopolymer suitable for human use, interacts directly with mucins in a Ca2+-sensitive manner to reduce CF mucus viscoelasticity and improve its transport. Notably, PAAG induced a linear structure of purified MUC5B and altered its sedimentation profile and viscosity, indicative of proper mucin expansion. In vivo, PAAG nebulization improved mucociliary transport in CF rats with delayed mucus clearance, and cleared mucus plugging in CF ferrets. This study demonstrates the potential use of a synthetic glycopolymer PAAG as a molecular agent that could benefit patients with a broad array of mucus diseases.
- Published
- 2019
- Full Text
- View/download PDF