Syndecan-2 exerts antifibrotic effects by promoting caveolin-1-mediated transforming growth factor-b receptor i internalization and inhibiting transforming growth factor-b1 signaling

Yuanyuan Shi, Bernadette R. Gochuico, Guoying Yu, Xiaomeng Tang, Juan C. Osorio, Isis E. Fernandez, Cristobal Risquez Cordovez, Avignat S. Patel, Ying Shi, Marc G. Wathelet, Andrew J. Goodwin, Jeffrey A. Haspel, Stefan W. Ryter, Eric M. Billings, Naftali Kaminski, Danielle Morse, Ivan O. Rosas

Research output: Contribution to journalArticle

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Abstract

Rationale: Alveolar transforming growth factor (TGF)-b1 signaling and expression of TGF-b1 target genes are increased in patients with idiopathic pulmonary fibrosis (IPF) and in animal models of pulmonary fibrosis. Internalization and degradation of TGF-b receptor TbRI inhibits TGF-b signaling and could attenuate development of experimental lung fibrosis. Objectives: To demonstrate that after experimental lung injury, humansyndecan- 2 confers antifibrotic effects by inhibiting TGF-b1 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-2dependent changes in epithelial cell TGF-b1 signaling, TGF-b1, 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-b1 signaling and downstream expression of TGF-b1 target genes, reducing extracellularmatrix production and alveolar epithelial cell apoptosis. In vitro, syndecan-2 promoted caveolin-1dependent internalization of TGF-b1 and TbRI in alveolar epithelial cells, which inhibited TGF-b1 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-1dependent TGF-b1 and TbRI internalization and inhibiting TGF-b1 signaling in alveolar epithelial cells. Hence, molecules that facilitate TbRI degradation via endocytosis represent potential therapies for pulmonary fibrosis.

Original languageEnglish (US)
Pages (from-to)831-841
Number of pages11
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume188
Issue number7
DOIs
StatePublished - Oct 1 2013

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Syndecan-2
Caveolin 1
Growth Factor Receptors
Transforming Growth Factors
Alveolar Epithelial Cells
Idiopathic Pulmonary Fibrosis
Alveolar Macrophages
Lung Injury
Caveolins
Pulmonary Fibrosis
Apoptosis
Transgenic Mice
Fibrosis
Syndecans
Epithelial Cells
Macrophages
Genes
Lung
Bleomycin

All Science Journal Classification (ASJC) codes

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

Cite this

Syndecan-2 exerts antifibrotic effects by promoting caveolin-1-mediated transforming growth factor-b receptor i internalization and inhibiting transforming growth factor-b1 signaling. / Shi, Yuanyuan; Gochuico, Bernadette R.; Yu, Guoying; Tang, Xiaomeng; Osorio, Juan C.; Fernandez, Isis E.; Risquez Cordovez, Cristobal; Patel, Avignat S.; Shi, Ying; Wathelet, Marc G.; Goodwin, Andrew J.; Haspel, Jeffrey A.; Ryter, Stefan W.; Billings, Eric M.; Kaminski, Naftali; Morse, Danielle; Rosas, Ivan O.

In: American Journal of Respiratory and Critical Care Medicine, Vol. 188, No. 7, 01.10.2013, p. 831-841.

Research output: Contribution to journalArticle

Shi, Y, Gochuico, BR, Yu, G, Tang, X, Osorio, JC, Fernandez, IE, Risquez Cordovez, C, Patel, AS, Shi, Y, Wathelet, MG, Goodwin, AJ, Haspel, JA, Ryter, SW, Billings, EM, Kaminski, N, Morse, D & Rosas, IO 2013, 'Syndecan-2 exerts antifibrotic effects by promoting caveolin-1-mediated transforming growth factor-b receptor i internalization and inhibiting transforming growth factor-b1 signaling', American Journal of Respiratory and Critical Care Medicine, vol. 188, no. 7, pp. 831-841. https://doi.org/10.1164/rccm.201303-0434OC
Shi, Yuanyuan ; Gochuico, Bernadette R. ; Yu, Guoying ; Tang, Xiaomeng ; Osorio, Juan C. ; Fernandez, Isis E. ; Risquez Cordovez, Cristobal ; Patel, Avignat S. ; Shi, Ying ; Wathelet, Marc G. ; Goodwin, Andrew J. ; Haspel, Jeffrey A. ; Ryter, Stefan W. ; Billings, Eric M. ; Kaminski, Naftali ; Morse, Danielle ; Rosas, Ivan O. / Syndecan-2 exerts antifibrotic effects by promoting caveolin-1-mediated transforming growth factor-b receptor i internalization and inhibiting transforming growth factor-b1 signaling. In: American Journal of Respiratory and Critical Care Medicine. 2013 ; Vol. 188, No. 7. pp. 831-841.
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abstract = "Rationale: Alveolar transforming growth factor (TGF)-b1 signaling and expression of TGF-b1 target genes are increased in patients with idiopathic pulmonary fibrosis (IPF) and in animal models of pulmonary fibrosis. Internalization and degradation of TGF-b receptor TbRI inhibits TGF-b signaling and could attenuate development of experimental lung fibrosis. Objectives: To demonstrate that after experimental lung injury, humansyndecan- 2 confers antifibrotic effects by inhibiting TGF-b1 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-2dependent changes in epithelial cell TGF-b1 signaling, TGF-b1, 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-b1 signaling and downstream expression of TGF-b1 target genes, reducing extracellularmatrix production and alveolar epithelial cell apoptosis. In vitro, syndecan-2 promoted caveolin-1dependent internalization of TGF-b1 and TbRI in alveolar epithelial cells, which inhibited TGF-b1 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-1dependent TGF-b1 and TbRI internalization and inhibiting TGF-b1 signaling in alveolar epithelial cells. Hence, molecules that facilitate TbRI degradation via endocytosis represent potential therapies for pulmonary fibrosis.",
author = "Yuanyuan Shi and Gochuico, {Bernadette R.} and Guoying Yu and Xiaomeng Tang and Osorio, {Juan C.} and Fernandez, {Isis E.} and {Risquez Cordovez}, Cristobal and Patel, {Avignat S.} and Ying Shi and Wathelet, {Marc G.} and Goodwin, {Andrew J.} and Haspel, {Jeffrey A.} and Ryter, {Stefan W.} and Billings, {Eric M.} and Naftali Kaminski and Danielle Morse and Rosas, {Ivan O.}",
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T1 - Syndecan-2 exerts antifibrotic effects by promoting caveolin-1-mediated transforming growth factor-b receptor i internalization and inhibiting transforming growth factor-b1 signaling

AU - Shi, Yuanyuan

AU - Gochuico, Bernadette R.

AU - Yu, Guoying

AU - Tang, Xiaomeng

AU - Osorio, Juan C.

AU - Fernandez, Isis E.

AU - Risquez Cordovez, Cristobal

AU - Patel, Avignat S.

AU - Shi, Ying

AU - Wathelet, Marc G.

AU - Goodwin, Andrew J.

AU - Haspel, Jeffrey A.

AU - Ryter, Stefan W.

AU - Billings, Eric M.

AU - Kaminski, Naftali

AU - Morse, Danielle

AU - Rosas, Ivan O.

PY - 2013/10/1

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N2 - Rationale: Alveolar transforming growth factor (TGF)-b1 signaling and expression of TGF-b1 target genes are increased in patients with idiopathic pulmonary fibrosis (IPF) and in animal models of pulmonary fibrosis. Internalization and degradation of TGF-b receptor TbRI inhibits TGF-b signaling and could attenuate development of experimental lung fibrosis. Objectives: To demonstrate that after experimental lung injury, humansyndecan- 2 confers antifibrotic effects by inhibiting TGF-b1 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-2dependent changes in epithelial cell TGF-b1 signaling, TGF-b1, 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-b1 signaling and downstream expression of TGF-b1 target genes, reducing extracellularmatrix production and alveolar epithelial cell apoptosis. In vitro, syndecan-2 promoted caveolin-1dependent internalization of TGF-b1 and TbRI in alveolar epithelial cells, which inhibited TGF-b1 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-1dependent TGF-b1 and TbRI internalization and inhibiting TGF-b1 signaling in alveolar epithelial cells. Hence, molecules that facilitate TbRI degradation via endocytosis represent potential therapies for pulmonary fibrosis.

AB - Rationale: Alveolar transforming growth factor (TGF)-b1 signaling and expression of TGF-b1 target genes are increased in patients with idiopathic pulmonary fibrosis (IPF) and in animal models of pulmonary fibrosis. Internalization and degradation of TGF-b receptor TbRI inhibits TGF-b signaling and could attenuate development of experimental lung fibrosis. Objectives: To demonstrate that after experimental lung injury, humansyndecan- 2 confers antifibrotic effects by inhibiting TGF-b1 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-2dependent changes in epithelial cell TGF-b1 signaling, TGF-b1, 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-b1 signaling and downstream expression of TGF-b1 target genes, reducing extracellularmatrix production and alveolar epithelial cell apoptosis. In vitro, syndecan-2 promoted caveolin-1dependent internalization of TGF-b1 and TbRI in alveolar epithelial cells, which inhibited TGF-b1 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-1dependent TGF-b1 and TbRI internalization and inhibiting TGF-b1 signaling in alveolar epithelial cells. Hence, molecules that facilitate TbRI degradation via endocytosis represent potential therapies for pulmonary fibrosis.

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