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An extracellular matrix fragment drives epithelial remodeling and airway hyper-responsiveness

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Title: An extracellular matrix fragment drives epithelial remodeling and airway hyper-responsiveness
Authors: Patel, D
Peiro, T
Shoemark, A
Akthar, S
Walker, S
Grabiec, A
Jackson, P
Hussell, T
Gaggar, A
Xu, X
Trevor, J
Li, J
Steele, C
Tavernier, G
Blalock, JE
Niven, R
Gregory, L
Simpson, A
Lloyd, C
Snelgrove, RJ
Item Type: Journal Article
Abstract: It is anticipated that bioactive fragments of the extracellular matrix (matrikines) can influence the development and progression of chronic diseases. The enzyme leukotriene A4 hydrolase (LTA4H) mediates opposing proinflammatory and anti-inflammatory activities, through the generation of leukotriene B4 (LTB4) and degradation of proneutrophilic matrikine Pro-Gly-Pro (PGP), respectively. We show that abrogation of LTB4 signaling ameliorated inflammation and airway hyperresponsiveness (AHR) in a murine asthma model, yet global loss of LTA4H exacerbated AHR, despite the absence of LTB4. This exacerbated AHR was attributable to a neutrophil-independent capacity of PGP to promote pathological airway epithelial remodeling. Thus, we demonstrate a disconnect between airway inflammation and AHR and the ability of a matrikine to promote an epithelial remodeling phenotype that negatively affects lung function. Subsequently, we show that substantial quantities of PGP are detectable in the sputum of moderate-severe asthmatics in two distinct cohorts of patients. These studies have implications for our understanding of remodeling phenotypes in asthma and may rationalize the failure of LTA4H inhibitors in the clinic.
Issue Date: 22-Aug-2018
Date of Acceptance: 20-Jul-2018
URI: http://hdl.handle.net/10044/1/62922
DOI: https://dx.doi.org/10.1126/scitranslmed.aaq0693
ISSN: 1946-6234
Publisher: American Association for the Advancement of Science
Journal / Book Title: Science Translational Medicine
Volume: 10
Issue: 455
Copyright Statement: © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works http://www.sciencemag.org/about/science-licenses-journal-article-reuseThis is an article distributed under the terms of the Science Journals Default License.
Sponsor/Funder: Wellcome Trust
Asthma UK
Wellcome Trust
Wellcome Trust
Funder's Grant Number: 095707/Z/11/Z
AUK-IG-2014-286
107059/Z/15/Z
209458/Z/17/Z
Keywords: Science & Technology
Life Sciences & Biomedicine
Cell Biology
Medicine, Research & Experimental
Research & Experimental Medicine
LEUKOTRIENE A(4) HYDROLASE
OBSTRUCTIVE PULMONARY-DISEASE
PROLINE-GLYCINE-PROLINE
NEUTROPHILIC INFLAMMATION
SEVERE ASTHMA
INDUCED SPUTUM
LUNG
B-4
CHEMOATTRACTANT
INHIBITOR
11 Medical And Health Sciences
06 Biological Sciences
Publication Status: Published
Appears in Collections:National Heart and Lung Institute
Faculty of Medicine



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