| First Author | Shi Y | Year | 2013 |
| Journal | Am J Respir Crit Care Med | Volume | 188 |
| Issue | 7 | Pages | 831-41 |
| PubMed ID | 23924348 | Mgi Jnum | J:297695 |
| Mgi Id | MGI:6479162 | Doi | 10.1164/rccm.201303-0434OC |
| Citation | Shi Y, et al. (2013) Syndecan-2 exerts antifibrotic effects by promoting caveolin-1-mediated transforming growth factor-beta receptor I internalization and inhibiting transforming growth factor-beta1 signaling. Am J Respir Crit Care Med 188(7):831-41 |
| abstractText | RATIONALE: Alveolar transforming growth factor (TGF)-beta1 signaling and expression of TGF-beta1 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 TbetaRI 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-beta1 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-beta1 signaling, TGF-beta1, and TbetaRI internalization and apoptosis. Wild-type 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-beta1 signaling and downstream expression of TGF-beta1 target genes, reducing extracellular matrix production and alveolar epithelial cell apoptosis. In vitro, syndecan-2 promoted caveolin-1-dependent internalization of TGF-beta1 and TbetaRI in alveolar epithelial cells, which inhibited TGF-beta1 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-beta1 and TbetaRI internalization and inhibiting TGF-beta1 signaling in alveolar epithelial cells. Hence, molecules that facilitate TbetaRI degradation via endocytosis represent potential therapies for pulmonary fibrosis. |
