Dataset Information

Syndecan-2 exerts antifibrotic effects by promoting caveolin-1-mediated transforming growth factor-? receptor I internalization and inhibiting transforming growth factor-?1 signaling.

ABSTRACT:

Rationale

Alveolar transforming growth factor (TGF)-?1 signaling and expression of TGF-?1 target genes are increased in patients with idiopathic pulmonary fibrosis (IPF) and in animal models of pulmonary fibrosis. Internalization and degradation of TGF-? receptor T?RI inhibits TGF-? 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-?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-?1 signaling, TGF-?1, and T?RI 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-?1 signaling and downstream expression of TGF-?1 target genes, reducing extracellular matrix production and alveolar epithelial cell apoptosis. In vitro, syndecan-2 promoted caveolin-1-dependent internalization of TGF-?1 and T?RI in alveolar epithelial cells, which inhibited TGF-?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-?1 and T?RI internalization and inhibiting TGF-?1 signaling in alveolar epithelial cells. Hence, molecules that facilitate T?RI degradation via endocytosis represent potential therapies for pulmonary fibrosis.

SUBMITTER: Shi Y

PROVIDER: S-EPMC3826270 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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Publications

Syndecan-2 exerts antifibrotic effects by promoting caveolin-1-mediated transforming growth factor-β receptor I internalization and inhibiting transforming growth factor-β1 signaling.

Shi Yuanyuan Y Gochuico Bernadette R BR Yu Guoying G Tang Xiaomeng X Osorio Juan C JC Fernandez Isis E IE Risquez Cristobal F CF Patel Avignat S AS Shi Ying Y Wathelet Marc G MG Goodwin Andrew J AJ Haspel Jeffrey A JA Ryter Stefan W SW Billings Eric M EM Kaminski Naftali N Morse Danielle D Rosas Ivan O IO

American journal of respiratory and critical care medicine 20131001 7

<h4>Rationale</h4>Alveolar transforming growth factor (TGF)-β1 signaling and expression of TGF-β1 target genes are increased in patients with idiopathic pulmonary fibrosis (IPF) and in animal models of pulmonary fibrosis. Internalization and degradation of TGF-β receptor TβRI inhibits TGF-β signaling and could attenuate development of experimental lung fibrosis.<h4>Objectives</h4>To demonstrate that after experimental lung injury, human syndecan-2 confers antifibrotic effects by inhibiting TGF-β ...[more]

PMID: 23924348

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