Airway fibroblasts in asthma manifest an invasive phenotype

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.