Airway fibroblasts in asthma manifest an invasive phenotype

Jennifer L. Ingram, Molly J. Huggins, Tony D. Church, Yuejuan Li, Dave C. Francisco, Simone Degan, Rafael Firszt, Denise M. Beaver, Njira L. Lugogo, Ying Wang, Mary E. Sunday, Paul W. Noble, Monica Kraft

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

Abstract

Rationale: 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 TH2 cytokine that directs many features of airway remodeling through TGF-β1 and MMPs. Objectives: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 (FEV1: 90 ± 3.6% pred) and 17 normal control subjects (FEV1: 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. Measurements and Main 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 receptorswereexpressed 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.

Original languageEnglish (US)
Pages (from-to)1625-1632
Number of pages8
JournalAmerican journal of respiratory and critical care medicine
Volume183
Issue number12
DOIs
StatePublished - Jun 15 2011

Keywords

  • Airway remodeling
  • Interleukin-13
  • Matrix metalloproteinase
  • Transforming growth factor-β

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

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