title: 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.
authors.affiliation: Departments of 1 Medicine.
authors.forename: Jennifer L
authors.identifier: http://orcid.org/0000-0001-7054-794X
authors.initials: JL
authors.lastname: Ingram
authors.affiliation: 2 Pediatrics and.
authors.forename: David
authors.initials: D
authors.lastname: Slade
authors.affiliation: Departments of 1 Medicine.
authors.forename: Tony D
authors.initials: TD
authors.lastname: Church
authors.affiliation: Departments of 1 Medicine.
authors.forename: Dave
authors.initials: D
authors.lastname: Francisco
authors.affiliation: 3 Pathology, Duke University Medical Center, Durham, North Carolina.
authors.forename: Karissa
authors.initials: K
authors.lastname: Heck
authors.affiliation: Departments of 1 Medicine.
authors.forename: R Wesley
authors.initials: RW
authors.lastname: Sigmon
authors.affiliation: Departments of 1 Medicine.
authors.forename: Michael
authors.initials: M
authors.lastname: Ghio
authors.affiliation: Departments of 1 Medicine.
authors.forename: Anays
authors.initials: A
authors.lastname: Murillo
authors.affiliation: 2 Pediatrics and.
authors.forename: Rafael
authors.initials: R
authors.lastname: Firszt
authors.affiliation: Departments of 1 Medicine.
authors.forename: Njira L
authors.initials: NL
authors.lastname: Lugogo
authors.affiliation: Departments of 1 Medicine.
authors.forename: Loretta
authors.initials: L
authors.lastname: Que
authors.affiliation: Departments of 1 Medicine.|3 Pathology, Duke University Medical Center, Durham, North Carolina.
authors.forename: Mary E
authors.initials: ME
authors.lastname: Sunday
authors.affiliation: Departments of 1 Medicine.
authors.forename: Monica
authors.initials: M
authors.lastname: Kraft
mesh_terms: D000328:Adult; D056151:Airway Remodeling / Q000187:drug effects*; D001249:Asthma / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D001985:Bronchial Provocation Tests; D016022:Case-Control Studies; D003120:Colorado; D015536:Down-Regulation; D004547:Elastic Tissue / Q000201:enzymology / Q000473:pathology; D004549:Elastin / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D005541:Forced Expiratory Volume; D006801:Humans; D018793:Interleukin-13 / Q000494:pharmacology*; D008168:Lung / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors / Q000494:pharmacology; D009657:North Carolina; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000187:drug effects; D014797:Vital Capacity
chemical_list: D018793:Interleukin-13; D061965:Matrix Metalloproteinase Inhibitors; D004549:Elastin; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; C522360:MMP1 protein, human; D020781:Matrix Metalloproteinase 1
keywords: asthma; elastin; fibroblast; interleukin-13; matrix metalloproteinase