期刊
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
卷 183, 期 12, 页码 1625-1632出版社
AMER THORACIC SOC
DOI: 10.1164/rccm.201009-1452OC
关键词
airway remodeling; interleukin-13; transforming growth factor-beta; matrix metalloproteinase
资金
- Parker B. Francis Family Foundation
- American Lung Association
- Merck
- ATS Grant Foundation
- American Asthma Foundation
- GlaxoSmithKline
- Bronchus
- GE Healthcare
- Asthmatx
- Genentech
- Novartis
- National Institutes of Health-NHLBI [HL-05-009]
- American Lung Association of North Carolina
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)-beta 1 and matrix metalloproteinases (MMPs). IL-13 is a key T(H)2 cytokine that directs many features of airway remodeling through TGF-beta 1 and MMPs. Objectives: We hypothesized that, in human asthma, IL-13 stimulates increased airway fibroblast invasiveness via TGF-beta 1 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-beta 1 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-beta 1 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-13R alpha 2 was reduced in asthma compared with normal control subjects. Conclusions: IL-13 potentiates airway fibroblast invasion through a mechanism involving TGF-b1 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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