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.

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Citation

Published Version (Please cite this version)

10.1165/rcmb.2014-0290oc

Publication Info

Ingram, Jennifer L, David Slade, Tony D Church, Dave Francisco, Karissa Heck, R Wesley Sigmon, Michael Ghio, Anays Murillo, et al. (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.

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Scholars@Duke

Que

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 the basic mechanisms of NO related lung disease, but also provide a rationale for targeted therapeutic use of NO.


Key words: nitrosative defense, lung injury, nitric oxide

Sunday

Mary Elizabeth Anne Sunday

Professor of Pathology

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 by many environmental exposures or autoimmune diseases, as well as idiopathic pulmonary fibrosis (IPF). There is no cure for PF. We seek to reverse fibrotic responses in lung.


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