Airway fibroblasts in asthma manifest an invasive phenotype.
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2011-06
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Abstract
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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.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 (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.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.Type
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Publication Info
Ingram, Jennifer L, Molly J Huggins, Tony D Church, Yuejuan Li, Dave C Francisco, Simone Degan, Rafael Firszt, Denise M Beaver, et al. (2011). Airway fibroblasts in asthma manifest an invasive phenotype. American journal of respiratory and critical care medicine, 183(12). pp. 1625–1632. 10.1164/rccm.201009-1452oc Retrieved from https://hdl.handle.net/10161/25439.
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Scholars@Duke
Jennifer Leigh Ingram
Dr. Ingram's research interests focus on the study of airway remodeling in human asthma. Proliferation, migration, and invasion of airway fibroblasts are key features of airway remodeling that contribute to diminished lung function over time. Dr. Ingram uses molecular biology approaches to define the effects of interleukin-13 (IL-13), a cytokine abundantly produced in the asthmatic airway, in the human airway fibroblast. She has identified important regulatory functions of several proteins prevalent in asthma that control fibroblast growth and pro-fibrotic growth factor production in response to IL-13. By understanding these pathways and their role in human asthma and the chronic effects of airway remodeling, novel treatment strategies may be developed.
Mary Elizabeth Anne Sunday
Oxygen (O2) is essential for life, but excessive oxygen causes tissue injury, scarring, aging, and death. We are studying mechanisms of injury mediated by O2-sensing pulmonary neuroendocrine cells, especially gastrin-releasing peptide (GRP). GRP secretion is induced by O2-related (oxidant) injury, leading to acute and chronic lung injury and pulmonary fibrosis (PF). Our key model is PF due to ionizing radiation to the thorax. This is clinically relevant to PF triggered by many environmental exposures or autoimmune diseases, as well as idiopathic pulmonary fibrosis (IPF). There is no cure for PF. We seek to reverse fibrotic responses in lung.
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