1. A glycopolymer improves vascoelasticity and mucociliary transport of abnormal cystic fibrosis mucus
- Author
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Susan E. Birket, Stacy M. Townsend, Kengyeh K. Chu, Guillermo J. Tearney, William P. Wiesmann, Steven M. Rowe, Justin Hanes, John F. Engelhardt, Gareth W. Hughes, T. Idil Apak Evans, Bradley H. Rosen, John P. Clancy, Heather Hathorne, John D. Watson, David J. Thornton, Hannah L. Bowers, Bryan Garcia, Carlo Santos, Courtney M. Fernandez-Petty, Shenda M. Baker, Hui Min Leung, William E. Swords, Emily Falk Libby, Caroline Ridley, Marina Mazur, and Yao Li
- Subjects
0301 basic medicine ,Cystic Fibrosis ,Mucociliary clearance ,Polymers ,Glycopolymer ,Cystic Fibrosis Transmembrane Conductance Regulator ,Respiratory Mucosa ,Cystic fibrosis ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Glucosamine ,medicine ,Extracellular ,Animals ,Humans ,Mice, Inbred CFTR ,Respiratory system ,Protein Structure, Quaternary ,Viscosity ,Mucin ,Ferrets ,General Medicine ,respiratory system ,medicine.disease ,Mucus ,Mucin-5B ,3. Good health ,Rats ,Disease Models, Animal ,030104 developmental biology ,chemistry ,Mucociliary Clearance ,030220 oncology & carcinogenesis ,Biophysics ,Research Article - 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 Ca(2+) 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 Ca(2+)-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