Journal
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
Volume 188, Issue 7, Pages 831-841Publisher
AMER THORACIC SOC
DOI: 10.1164/rccm.201303-0434OC
Keywords
idiopathic pulmonary fibrosis; TGF-beta 1 signaling; syndecan-2; alveolar macrophage
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Funding
- Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health
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Rationale: Alveolar transforming growth factor (TGF)-beta 1 signaling and expression of TGF-beta 1 target genes are increased in patients with idiopathic pulmonary fibrosis (IPF) and in animal models of pulmonary fibrosis. Internalization and degradation of TGF-beta receptor TbRI inhibits TGF-beta signaling and could attenuate development of experimental lung fibrosis. Objectives: To demonstrate that after experimental lung injury, human syndecan-2 confers antifibrotic effects by inhibiting TGF-beta 1 signaling in alveolar epithelial cells. Methods: Microarray assays were performed to identify genes differentially expressed in alveolar macrophages of patients with IPF versus control subjects. Transgenic mice that constitutively overexpress human syndecan-2 in macrophages were developed to test the antifibrotic properties of syndecan-2. In vitro assays were performed to determine syndecan-2-dependent changes in epithelial cell TGF-beta 1 signaling, TGF-beta 1, and TbRI internalization and apoptosis. Wildtype mice were treated with recombinant human syndecan-2 during the fibrotic phase of bleomycin-induced lung injury. Measurements and Main Results: We observed significant increases in alveolar macrophage syndecan-2 levels in patients with IPF. Macrophage-specific overexpression of human syndecan-2 in transgenic mice conferred antifibrotic effects after lung injury by inhibiting TGF-beta 1 signaling and downstream expression of TGF-beta 1 target genes, reducing extracellular matrix production and alveolar epithelial cell apoptosis. In vitro, syndecan-2 promoted caveolin-1-dependent internalization of TGF-beta 1 and TbRI in alveolar epithelial cells, which inhibited TGF-beta 1 signaling and epithelial cell apoptosis. Therapeutic administration of human syndecan-2 abrogated lung fibrosis in mice. Conclusions: Alveolar macrophage syndecan-2 exerts antifibrotic effects by promoting caveolin-1-dependent TGF-beta 1 and TbRI internalization and inhibiting TGF-beta 1 signaling in alveolar epithelial cells. Hence, molecules that facilitate TbRI degradation via endocytosis represent potential therapies for pulmonary fibrosis.
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