Airway fibroblasts in asthma manifest an invasive phenotype
JL Ingram, MJ Huggins, TD Church, Y Li… - American journal of …, 2011 - atsjournals.org
JL Ingram, MJ Huggins, TD Church, Y Li, DC Francisco, S Degan, R Firszt, DM Beaver…
American journal of respiratory and critical care medicine, 2011•atsjournals.orgRationale: 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 …
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 …
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 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.
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