Ingram, Jennifer LHuggins, Molly JChurch, Tony DLi, YuejuanFrancisco, Dave CDegan, SimoneFirszt, RafaelBeaver, Denise MLugogo, Njira LWang, YingSunday, Mary ENoble, Paul WKraft, Monica2022-07-012022-07-012011-061073-449X1535-4970https://hdl.handle.net/10161/25439<h4>Rationale</h4>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.<h4>Objectives</h4>We hypothesized that, in human asthma, IL-13 stimulates increased airway fibroblast invasiveness via TGF-β1 and MMPs in asthma compared with normal controls.<h4>Methods</h4>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.<h4>Measurements and main results</h4>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.<h4>Conclusions</h4>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.BronchiCells, CulturedFibroblastsHumansAsthmaMatrix MetalloproteinasesInterleukin-13Flow CytometryImmunohistochemistryAdultFemaleMaleTransforming Growth Factor beta1Receptors, Interleukin-13Airway RemodelingJournal article2022-07-01