| Literature DB >> 30996141 |
Courtney M Fernandez-Petty1, Gareth W Hughes2, Hannah L Bowers1, John D Watson1, Bradley H Rosen3,4, Stacy M Townsend5, Carlo Santos5, Caroline E Ridley2, Kengyeh K Chu6,7,8,9,10, Susan E. Birket1,11, Yao Li1,11, Hui Min Leung6,7,8,9,10, Marina Mazur11, Bryan A Garcia1,11, T Idil Apak Evans3, Emily Falk Libby11, Heather Hathorne11,12, Justin Hanes13, Guillermo J Tearney6,7,8,9,10, John P Clancy14, John F Engelhardt3,4, William E Swords1,11, David J Thornton2, William P Wiesmann5, Shenda M Baker5, Steven M Rowe1,11,12,15.
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.Entities:
Keywords: Drug therapy; Genetic diseases; Genetics; Pulmonology; Respiration
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Year: 2019 PMID： 30996141 PMCID： PMC6538343 DOI： 10.1172/jci.insight.125954
Source DB: PubMed Journal: JCI Insight ISSN： 2379-3708