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S-maltoheptaose targets syndecan-bound effectors to reduce smoking-related neutrophilic inflammation

Cigarette smoke induces injury and neutrophilic inflammation in the airways of smokers. The stability and activity of inflammatory effectors, IL8 and neutrophil elastase (NE), can be prolonged by binding to airway heparan sulfate (HS)/syndecan-1, posing risk for developing chronic obstructive pulmon...

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Autores principales: Lam, David CL, Chan, Stanley CH, Mak, Judith CW, Freeman, Craig, Ip, Mary SM, Shum, Daisy KY
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4530444/
https://www.ncbi.nlm.nih.gov/pubmed/26256047
http://dx.doi.org/10.1038/srep12945
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author Lam, David CL
Chan, Stanley CH
Mak, Judith CW
Freeman, Craig
Ip, Mary SM
Shum, Daisy KY
author_facet Lam, David CL
Chan, Stanley CH
Mak, Judith CW
Freeman, Craig
Ip, Mary SM
Shum, Daisy KY
author_sort Lam, David CL
collection PubMed
description Cigarette smoke induces injury and neutrophilic inflammation in the airways of smokers. The stability and activity of inflammatory effectors, IL8 and neutrophil elastase (NE), can be prolonged by binding to airway heparan sulfate (HS)/syndecan-1, posing risk for developing chronic obstructive pulmonary disease(COPD). We hypothesize that antagonizing HS/syndecan-1 binding of the inflammatory effectors could reduce smoking-related neutrophil-mediated airway inflammation. Analysis of bronchoalveolar lavage fluid(BALF) of COPD patients found both total and unopposed NE levels to be significantly higher among smokers with COPD than non-COPD subjects. Similar NE burden was observed in smoke-exposed rats compared to sham air controls. We chose sulfated-maltoheptaose(SM), a heparin-mimetic, to antagonize HS/sydecan-1 binding of the inflammatory mediators in airway fluids and lung tissues of the smoke-exposed rat model. Airway treatment with SM resulted in displacement of CINC-1 and NE from complexation with bronchio-epithelial HS/syndecan-1, dissipating the chemokine gradient for neutrophil flux across to the bronchial lumen. Following SM displacement of NE from shed HS/syndecan-1 in bronchial fluids, NE became accessible to inhibition by α(1)-antitrypsin endogenous in test samples. The antagonistic actions of SM against syndecan-1 binding of NE and CINC-1 in smoke-exposed airways suggest new therapeutic opportunities for modulating airway inflammation in smokers with SM delivery.
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spelling pubmed-45304442015-08-11 S-maltoheptaose targets syndecan-bound effectors to reduce smoking-related neutrophilic inflammation Lam, David CL Chan, Stanley CH Mak, Judith CW Freeman, Craig Ip, Mary SM Shum, Daisy KY Sci Rep Article Cigarette smoke induces injury and neutrophilic inflammation in the airways of smokers. The stability and activity of inflammatory effectors, IL8 and neutrophil elastase (NE), can be prolonged by binding to airway heparan sulfate (HS)/syndecan-1, posing risk for developing chronic obstructive pulmonary disease(COPD). We hypothesize that antagonizing HS/syndecan-1 binding of the inflammatory effectors could reduce smoking-related neutrophil-mediated airway inflammation. Analysis of bronchoalveolar lavage fluid(BALF) of COPD patients found both total and unopposed NE levels to be significantly higher among smokers with COPD than non-COPD subjects. Similar NE burden was observed in smoke-exposed rats compared to sham air controls. We chose sulfated-maltoheptaose(SM), a heparin-mimetic, to antagonize HS/sydecan-1 binding of the inflammatory mediators in airway fluids and lung tissues of the smoke-exposed rat model. Airway treatment with SM resulted in displacement of CINC-1 and NE from complexation with bronchio-epithelial HS/syndecan-1, dissipating the chemokine gradient for neutrophil flux across to the bronchial lumen. Following SM displacement of NE from shed HS/syndecan-1 in bronchial fluids, NE became accessible to inhibition by α(1)-antitrypsin endogenous in test samples. The antagonistic actions of SM against syndecan-1 binding of NE and CINC-1 in smoke-exposed airways suggest new therapeutic opportunities for modulating airway inflammation in smokers with SM delivery. Nature Publishing Group 2015-08-10 /pmc/articles/PMC4530444/ /pubmed/26256047 http://dx.doi.org/10.1038/srep12945 Text en Copyright © 2015, Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Lam, David CL
Chan, Stanley CH
Mak, Judith CW
Freeman, Craig
Ip, Mary SM
Shum, Daisy KY
S-maltoheptaose targets syndecan-bound effectors to reduce smoking-related neutrophilic inflammation
title S-maltoheptaose targets syndecan-bound effectors to reduce smoking-related neutrophilic inflammation
title_full S-maltoheptaose targets syndecan-bound effectors to reduce smoking-related neutrophilic inflammation
title_fullStr S-maltoheptaose targets syndecan-bound effectors to reduce smoking-related neutrophilic inflammation
title_full_unstemmed S-maltoheptaose targets syndecan-bound effectors to reduce smoking-related neutrophilic inflammation
title_short S-maltoheptaose targets syndecan-bound effectors to reduce smoking-related neutrophilic inflammation
title_sort s-maltoheptaose targets syndecan-bound effectors to reduce smoking-related neutrophilic inflammation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4530444/
https://www.ncbi.nlm.nih.gov/pubmed/26256047
http://dx.doi.org/10.1038/srep12945
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