Role of matrix metalloproteinases-1 and-2 in interleukin-13-suppressed elastin in airway fibroblasts in asthma

Jennifer L. Ingram, David Slade, Tony D. Church, Dave Francisco, Karissa Heck, R. Wesley Sigmon, Michael Ghio, Anays Murillo, Rafael Firszt, Njira L. Lugogo, Loretta Que, Mary E. Sunday, Monica Kraft

Research output: Contribution to journalArticle

11 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)41-50
Number of pages10
JournalAmerican journal of respiratory cell and molecular biology
Volume54
Issue number1
DOIs
StatePublished - Jan 2016

Keywords

  • Asthma
  • Elastin
  • Fibroblast
  • Interleukin-13
  • Matrix metalloproteinase

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

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  • Cite this

    Ingram, J. L., Slade, D., Church, T. D., Francisco, D., Heck, K., Wesley Sigmon, R., Ghio, M., Murillo, A., Firszt, R., Lugogo, N. L., Que, L., Sunday, M. E., & Kraft, M. (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), 41-50. https://doi.org/10.1165/rcmb.2014-0290OC