A glycopolymer improves vascoelasticity and mucociliary transport of abnormal cystic fibrosis mucus

Courtney M. Fernandez-Petty, Gareth W. Hughes, Hannah L. Bowers, John D. Watson, Bradley H. Rosen, Stacy M. Townsend, Carlo Santos, Caroline E. Ridley, Kengyeh K. Chu, Susan E. Birket, Yao Li, Hui Min Leung, Marina Mazur, Bryan A. Garcia, T. Idil Apak Evans, Emily Falk Libby, Heather Hathorne, Justin Hanes, Guillermo J. Tearney, John P. ClancyJohn F. Engelhardt, William E. Swords, David J. Thornton, William P. Wiesmann, Shenda M. Baker, Steven M. Rowe

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article numbere125954
JournalJCI Insight
Volume4
Issue number8
DOIs
StatePublished - Jan 1 2019

Fingerprint

Mucociliary Clearance
Mucus
Cystic Fibrosis
Mucins
Glucosamine
Viscosity
Ferrets
Biopolymers
Dehydration
Adhesives
Respiratory System
Gastrointestinal Tract
Lung

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Fernandez-Petty, C. M., Hughes, G. W., Bowers, H. L., Watson, J. D., Rosen, B. H., Townsend, S. M., ... Rowe, S. M. (2019). A glycopolymer improves vascoelasticity and mucociliary transport of abnormal cystic fibrosis mucus. JCI Insight, 4(8), [e125954]. https://doi.org/10.1172/jci.insight.125954

A glycopolymer improves vascoelasticity and mucociliary transport of abnormal cystic fibrosis mucus. / Fernandez-Petty, Courtney M.; Hughes, Gareth W.; Bowers, Hannah L.; Watson, John D.; Rosen, Bradley H.; Townsend, Stacy M.; Santos, Carlo; Ridley, Caroline E.; Chu, Kengyeh K.; Birket, Susan E.; Li, Yao; Leung, Hui Min; Mazur, Marina; Garcia, Bryan A.; Evans, T. Idil Apak; Libby, Emily Falk; Hathorne, Heather; Hanes, Justin; Tearney, Guillermo J.; Clancy, John P.; Engelhardt, John F.; Swords, William E.; Thornton, David J.; Wiesmann, William P.; Baker, Shenda M.; Rowe, Steven M.

In: JCI Insight, Vol. 4, No. 8, e125954, 01.01.2019.

Research output: Contribution to journalArticle

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 & Rowe, SM 2019, 'A glycopolymer improves vascoelasticity and mucociliary transport of abnormal cystic fibrosis mucus', JCI Insight, vol. 4, no. 8, e125954. https://doi.org/10.1172/jci.insight.125954
Fernandez-Petty CM, Hughes GW, Bowers HL, Watson JD, Rosen BH, Townsend SM et al. A glycopolymer improves vascoelasticity and mucociliary transport of abnormal cystic fibrosis mucus. JCI Insight. 2019 Jan 1;4(8). e125954. https://doi.org/10.1172/jci.insight.125954
Fernandez-Petty, Courtney M. ; Hughes, Gareth W. ; Bowers, Hannah L. ; Watson, John D. ; Rosen, Bradley H. ; Townsend, Stacy M. ; Santos, Carlo ; Ridley, Caroline E. ; Chu, Kengyeh K. ; Birket, Susan E. ; Li, Yao ; Leung, Hui Min ; Mazur, Marina ; Garcia, Bryan A. ; Evans, T. Idil Apak ; Libby, Emily Falk ; Hathorne, Heather ; Hanes, Justin ; Tearney, Guillermo J. ; Clancy, John P. ; Engelhardt, John F. ; Swords, William E. ; Thornton, David J. ; Wiesmann, William P. ; Baker, Shenda M. ; Rowe, Steven M. / A glycopolymer improves vascoelasticity and mucociliary transport of abnormal cystic fibrosis mucus. In: JCI Insight. 2019 ; Vol. 4, No. 8.
@article{2484b31fdfef4973909eae5b3ce5ec61,
title = "A glycopolymer improves vascoelasticity and mucociliary transport of abnormal cystic fibrosis mucus",
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.",
author = "Fernandez-Petty, {Courtney M.} and Hughes, {Gareth W.} and Bowers, {Hannah L.} and Watson, {John D.} and Rosen, {Bradley H.} and Townsend, {Stacy M.} and Carlo Santos and Ridley, {Caroline E.} and Chu, {Kengyeh K.} and Birket, {Susan E.} and Yao Li and Leung, {Hui Min} and Marina Mazur and Garcia, {Bryan A.} and Evans, {T. Idil Apak} and Libby, {Emily Falk} and Heather Hathorne and Justin Hanes and Tearney, {Guillermo J.} and Clancy, {John P.} and Engelhardt, {John F.} and Swords, {William E.} and Thornton, {David J.} and Wiesmann, {William P.} and Baker, {Shenda M.} and Rowe, {Steven M.}",
year = "2019",
month = "1",
day = "1",
doi = "10.1172/jci.insight.125954",
language = "English (US)",
volume = "4",
journal = "JCI insight",
issn = "2379-3708",
publisher = "The American Society for Clinical Investigation",
number = "8",

}

TY - JOUR

T1 - A glycopolymer improves vascoelasticity and mucociliary transport of abnormal cystic fibrosis mucus

AU - Fernandez-Petty, Courtney M.

AU - Hughes, Gareth W.

AU - Bowers, Hannah L.

AU - Watson, John D.

AU - Rosen, Bradley H.

AU - Townsend, Stacy M.

AU - Santos, Carlo

AU - Ridley, Caroline E.

AU - Chu, Kengyeh K.

AU - Birket, Susan E.

AU - Li, Yao

AU - Leung, Hui Min

AU - Mazur, Marina

AU - Garcia, Bryan A.

AU - Evans, T. Idil Apak

AU - Libby, Emily Falk

AU - Hathorne, Heather

AU - Hanes, Justin

AU - Tearney, Guillermo J.

AU - Clancy, John P.

AU - Engelhardt, John F.

AU - Swords, William E.

AU - Thornton, David J.

AU - Wiesmann, William P.

AU - Baker, Shenda M.

AU - Rowe, Steven M.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85070660395&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85070660395&partnerID=8YFLogxK

U2 - 10.1172/jci.insight.125954

DO - 10.1172/jci.insight.125954

M3 - Article

C2 - 30996141

AN - SCOPUS:85070660395

VL - 4

JO - JCI insight

JF - JCI insight

SN - 2379-3708

IS - 8

M1 - e125954

ER -