Role of Matrix Metalloproteinases-1 and -2 in Interleukin-13-Suppressed Elastin in Airway Fibroblasts in Asthma.
Abstract
Elastin synthesis and degradation in the airway and lung parenchyma contribute to
airway mechanics, including airway patency and elastic recoil. IL-13 mediates many
features of asthma pathobiology, including airway remodeling, but the effects of IL-13
on elastin architecture in the airway wall are not known. We hypothesized that IL-13
modulates elastin expression in airway fibroblasts from subjects with allergic asthma.
Twenty-five subjects with mild asthma (FEV1, 89 ± 3% predicted) and 30 normal control
subjects (FEV1, 102 ± 2% predicted) underwent bronchoscopy with endobronchial biopsy.
Elastic fibers were visualized in airway biopsy specimens using Weigert's resorcin-fuchsin
elastic stain. Airway fibroblasts were exposed to IL-13; a pan-matrix metalloproteinase
(MMP) inhibitor (GM6001); specific inhibitors to MMP-1, -2, -3, and -8; and combinations
of IL-13 with MMP inhibitors in separate conditions in serum-free media for 48 hours.
Elastin (ELN) expression as well as MMP secretion and activity were quantified. Results
of this study show that elastic fiber staining of airway biopsy tissue was significantly
associated with methacholine PC20 (i.e., the provocative concentration of methacholine
resulting in a 20% fall in FEV1 levels) in patients with asthma. IL-13 significantly
suppressed ELN expression in asthmatic airway fibroblasts as compared with normal
control fibroblasts. The effect of IL-13 on ELN expression was significantly correlated
with postbronchodilator FEV1/FVC in patients with asthma. MMP inhibition significantly
stimulated ELN expression in patients with asthma as compared with normal control
subjects. Specific inhibition of MMP-1 and MMP-2, but not MMP-3 or MMP-8, reversed
the IL-13-induced suppression of ELN expression. In asthma, MMP-1 and MMP-2 mediate
IL-13-induced suppression of ELN expression in airway fibroblasts.
Type
Journal articleSubject
LungElastic Tissue
Fibroblasts
Humans
Asthma
Elastin
Interleukin-13
Bronchial Provocation Tests
Vital Capacity
Forced Expiratory Volume
Severity of Illness Index
Case-Control Studies
Signal Transduction
Down-Regulation
Adult
North Carolina
Colorado
Female
Male
Matrix Metalloproteinase 2
Matrix Metalloproteinase 1
Airway Remodeling
Matrix Metalloproteinase Inhibitors
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https://hdl.handle.net/10161/25437Published Version (Please cite this version)
10.1165/rcmb.2014-0290ocPublication Info
Ingram, Jennifer L; Slade, David; Church, Tony D; Francisco, Dave; Heck, Karissa;
Sigmon, R Wesley; ... Kraft, Monica (2016). Role of Matrix Metalloproteinases-1 and -2 in Interleukin-13-Suppressed Elastin in
Airway Fibroblasts in Asthma. American journal of respiratory cell and molecular biology, 54(1). pp. 41-50. 10.1165/rcmb.2014-0290oc. Retrieved from https://hdl.handle.net/10161/25437.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Show full item recordScholars@Duke
Jennifer Leigh Ingram
Associate Professor in Medicine
Dr. Ingram's research interests focus on the study of airway remodeling in human asthma.
Proliferation, migration, and invasion of airway fibroblasts are key features of airway
remodeling that contribute to diminished lung function over time. Dr. Ingram uses
molecular biology approaches to define the effects of interleukin-13 (IL-13), a cytokine
abundantly produced in the asthmatic airway, in the human airway fibroblast. She has
identified important regulatory functions of several proteins
Monica Kraft
Adjunct Professor in the Department of Medicine
Njira Lucia Lugogo
Adjunct Assistant Professor in the Department of Medicine
My research focus is asthma. I perform clinical trials in asthma and I am interested
in working on new therapies for patients with severe asthma. I am also interested
in the role of obesity on asthma phenotypes and biomarkers.
Loretta Georgina Que
Professor of Medicine
My research interests focus on studying the role of nitric oxide and related enzymes
in the pathogenesis of lung disease, specifically that caused by nitrosative/oxidative
stress. Proposed studies are performed in cell culture and applied to animal models
of disease, then examined in human disease where relevant. It is our hope that by
better understanding the role of NO and reactive nitrogen species in mediating inflammation,
and regulating cell signaling, that we will not only help to unravel
Mary Elizabeth Anne Sunday
Professor of Pathology
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Oxygen (O2) is essential for life, but excessive oxygen causes tissue injury, scarring,
aging, and death. We are studying mechanisms of injury mediated by O2-sensing pulmonary
neuroendocrine cells, especially gastrin-releasing peptide (GRP). GRP secretion is
induced by O2-related (oxidant) injury, leading to acute and chronic lung injury and
pulmonary fibrosis (PF). Our key model is PF due to ionizing radiation to the thorax.
This is clinically relevant to PF triggered b
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