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Airway bacteria drive a progressive COPD-like phenotype in mice with polymeric immunoglobulin receptor deficiency

Mechanisms driving persistent airway inflammation in chronic obstructive pulmonary disease (COPD) are incompletely understood. As secretory immunoglobulin A (SIgA) deficiency in small airways has been reported in COPD patients, we hypothesized that immunobarrier dysfunction resulting from reduced SI...

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Autores principales: Richmond, Bradley W., Brucker, Robert M., Han, Wei, Du, Rui-Hong, Zhang, Yongqin, Cheng, Dong-Sheng, Gleaves, Linda, Abdolrasulnia, Rasul, Polosukhina, Dina, Clark, Peter E., Bordenstein, Seth R., Blackwell, Timothy S., Polosukhin, Vasiliy V.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4822073/
https://www.ncbi.nlm.nih.gov/pubmed/27046438
http://dx.doi.org/10.1038/ncomms11240
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author Richmond, Bradley W.
Brucker, Robert M.
Han, Wei
Du, Rui-Hong
Zhang, Yongqin
Cheng, Dong-Sheng
Gleaves, Linda
Abdolrasulnia, Rasul
Polosukhina, Dina
Clark, Peter E.
Bordenstein, Seth R.
Blackwell, Timothy S.
Polosukhin, Vasiliy V.
author_facet Richmond, Bradley W.
Brucker, Robert M.
Han, Wei
Du, Rui-Hong
Zhang, Yongqin
Cheng, Dong-Sheng
Gleaves, Linda
Abdolrasulnia, Rasul
Polosukhina, Dina
Clark, Peter E.
Bordenstein, Seth R.
Blackwell, Timothy S.
Polosukhin, Vasiliy V.
author_sort Richmond, Bradley W.
collection PubMed
description Mechanisms driving persistent airway inflammation in chronic obstructive pulmonary disease (COPD) are incompletely understood. As secretory immunoglobulin A (SIgA) deficiency in small airways has been reported in COPD patients, we hypothesized that immunobarrier dysfunction resulting from reduced SIgA contributes to chronic airway inflammation and disease progression. Here we show that polymeric immunoglobulin receptor-deficient (pIgR(−/−)) mice, which lack SIgA, spontaneously develop COPD-like pathology as they age. Progressive airway wall remodelling and emphysema in pIgR(−/−) mice are associated with an altered lung microbiome, bacterial invasion of the airway epithelium, NF-κB activation, leukocyte infiltration and increased expression of matrix metalloproteinase-12 and neutrophil elastase. Re-derivation of pIgR(−/−) mice in germ-free conditions or treatment with the anti-inflammatory phosphodiesterase-4 inhibitor roflumilast prevents COPD-like lung inflammation and remodelling. These findings show that pIgR/SIgA deficiency in the airways leads to persistent activation of innate immune responses to resident lung microbiota, driving progressive small airway remodelling and emphysema.
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spelling pubmed-48220732016-04-17 Airway bacteria drive a progressive COPD-like phenotype in mice with polymeric immunoglobulin receptor deficiency Richmond, Bradley W. Brucker, Robert M. Han, Wei Du, Rui-Hong Zhang, Yongqin Cheng, Dong-Sheng Gleaves, Linda Abdolrasulnia, Rasul Polosukhina, Dina Clark, Peter E. Bordenstein, Seth R. Blackwell, Timothy S. Polosukhin, Vasiliy V. Nat Commun Article Mechanisms driving persistent airway inflammation in chronic obstructive pulmonary disease (COPD) are incompletely understood. As secretory immunoglobulin A (SIgA) deficiency in small airways has been reported in COPD patients, we hypothesized that immunobarrier dysfunction resulting from reduced SIgA contributes to chronic airway inflammation and disease progression. Here we show that polymeric immunoglobulin receptor-deficient (pIgR(−/−)) mice, which lack SIgA, spontaneously develop COPD-like pathology as they age. Progressive airway wall remodelling and emphysema in pIgR(−/−) mice are associated with an altered lung microbiome, bacterial invasion of the airway epithelium, NF-κB activation, leukocyte infiltration and increased expression of matrix metalloproteinase-12 and neutrophil elastase. Re-derivation of pIgR(−/−) mice in germ-free conditions or treatment with the anti-inflammatory phosphodiesterase-4 inhibitor roflumilast prevents COPD-like lung inflammation and remodelling. These findings show that pIgR/SIgA deficiency in the airways leads to persistent activation of innate immune responses to resident lung microbiota, driving progressive small airway remodelling and emphysema. Nature Publishing Group 2016-04-05 /pmc/articles/PMC4822073/ /pubmed/27046438 http://dx.doi.org/10.1038/ncomms11240 Text en Copyright © 2016, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. 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
Richmond, Bradley W.
Brucker, Robert M.
Han, Wei
Du, Rui-Hong
Zhang, Yongqin
Cheng, Dong-Sheng
Gleaves, Linda
Abdolrasulnia, Rasul
Polosukhina, Dina
Clark, Peter E.
Bordenstein, Seth R.
Blackwell, Timothy S.
Polosukhin, Vasiliy V.
Airway bacteria drive a progressive COPD-like phenotype in mice with polymeric immunoglobulin receptor deficiency
title Airway bacteria drive a progressive COPD-like phenotype in mice with polymeric immunoglobulin receptor deficiency
title_full Airway bacteria drive a progressive COPD-like phenotype in mice with polymeric immunoglobulin receptor deficiency
title_fullStr Airway bacteria drive a progressive COPD-like phenotype in mice with polymeric immunoglobulin receptor deficiency
title_full_unstemmed Airway bacteria drive a progressive COPD-like phenotype in mice with polymeric immunoglobulin receptor deficiency
title_short Airway bacteria drive a progressive COPD-like phenotype in mice with polymeric immunoglobulin receptor deficiency
title_sort airway bacteria drive a progressive copd-like phenotype in mice with polymeric immunoglobulin receptor deficiency
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4822073/
https://www.ncbi.nlm.nih.gov/pubmed/27046438
http://dx.doi.org/10.1038/ncomms11240
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