title: Airway fibroblasts in asthma manifest an invasive phenotype.
abstract: BACKGROUND
  Invasive cell phenotypes have been demonstrated in malignant transformation, but not in other diseases, such as asthma. Cellular invasiveness is thought to be mediated by transforming growth factor (TGF)-β1 and matrix metalloproteinases (MMPs). IL-13 is a key T(H)2 cytokine that directs many features of airway remodeling through TGF-β1 and MMPs.
  
  
  OBJECTIVE
  We hypothesized that, in human asthma, IL-13 stimulates increased airway fibroblast invasiveness via TGF-β1 and MMPs in asthma compared with normal controls.
  
  
  METHODS
  Fibroblasts were cultured from endobronchial biopsies in 20 subjects with mild asthma (FEV(1): 90 ± 3.6% pred) and 17 normal control subjects (FEV(1): 102 ± 2.9% pred) who underwent bronchoscopy. Airway fibroblast invasiveness was investigated using Matrigel chambers. IL-13 or IL-13 with TGF-β1 neutralizing antibody or pan-MMP inhibitor (GM6001) was added to the lower chamber as a chemoattractant. Flow cytometry and immunohistochemistry were performed in a subset of subjects to evaluate IL-13 receptor levels.
  
  
  RESULTS
  IL-13 significantly stimulated invasion in asthmatic airway fibroblasts, compared with normal control subjects. Inhibitors of both TGF-β1 and MMPs blocked IL-13-induced invasion in asthma, but had no effect in normal control subjects. At baseline, in airway tissue, IL-13 receptors were expressed in significantly higher levels in asthma, compared with normal control subjects. In airway fibroblasts, baseline IL-13Rα2 was reduced in asthma compared with normal control subjects.
  
  
  CONCLUSIONS
  IL-13 potentiates airway fibroblast invasion through a mechanism involving TGF-β1 and MMPs. IL-13 receptor subunits are differentially expressed in asthma. These effects may result in IL-13-directed airway remodeling in asthma.
authors.affiliation: Department of Medicine, Duke University Medical Center, 201 MSRB 1, Research Drive, Box 2641, Durham, NC 27710, USA. jennifer.ingram@duke.edu
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Ingram
authors.forename: Molly J
authors.initials: MJ
authors.lastname: Huggins
authors.forename: Tony D
authors.initials: TD
authors.lastname: Church
authors.forename: Yuejuan
authors.initials: Y
authors.lastname: Li
authors.forename: Dave C
authors.initials: DC
authors.lastname: Francisco
authors.forename: Simone
authors.initials: S
authors.lastname: Degan
authors.forename: Rafael
authors.initials: R
authors.lastname: Firszt
authors.forename: Denise M
authors.initials: DM
authors.lastname: Beaver
authors.forename: Njira L
authors.initials: NL
authors.lastname: Lugogo
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Mary E
authors.initials: ME
authors.lastname: Sunday
authors.forename: Paul W
authors.initials: PW
authors.lastname: Noble
authors.forename: Monica
authors.initials: M
authors.lastname: Kraft
mesh_terms: D000328:Adult; D056151:Airway Remodeling / Q000502:physiology; D001249:Asthma / Q000473:pathology*; D001980:Bronchi / Q000473:pathology; D002478:Cells, Cultured; D005260:Female; D005347:Fibroblasts / Q000502:physiology*; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D018793:Interleukin-13 / Q000502:physiology*; D008297:Male; D020782:Matrix Metalloproteinases / Q000502:physiology; D053660:Receptors, Interleukin-13 / Q000032:analysis; D053773:Transforming Growth Factor beta1 / Q000502:physiology
chemical_list: D018793:Interleukin-13; D053660:Receptors, Interleukin-13; D053773:Transforming Growth Factor beta1; D020782:Matrix Metalloproteinases