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Fibrogenesis & Tissue Repair

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Open Access 01-12-2013 | Research

Secreted protein acidic and rich in cysteine (SPARC) is upregulated by transforming growth factor (TGF)-β and is required for TGF-β-induced hydrogen peroxide production in fibroblasts

Authors: Saiko Shibata, Junichi Ishiyama

Published in: Fibrogenesis & Tissue Repair | Issue 1/2013

Abstract

Background

Idiopathic pulmonary fibrosis (IPF) is a poorly understood progressive disease characterized by the recurrent damage of alveolar epithelial cells as well as inappropriate expansion and activation of fibroblasts resulting in pronounced extracellular matrix (ECM) deposition. Although recent studies have indicated the involvement of secreted protein acidic and rich in cysteine (SPARC), a matricellular protein regulating ECM deposition, in the pathogenesis of fibrosis, factors regulating SPARC expression or roles of SPARC in fibrosis have not been fully elucidated.

Results

Among the profibrotic factors examined in cultured fibroblasts, we showed that SPARC expression was upregulated mainly by transforming growth factor (TGF)-β. We also showed that expression of SPARC in the lung was upregulated in the murine bleomycin-induced pulmonary fibrosis model, which was inhibited by TGF-β receptor I inhibitor. Knockdown of SPARC in fibroblasts using siRNA or treatment with the antioxidant N-acetylcysteine attenuated epithelial cell injury induced by TGF-β-activated fibroblasts in a coculture system. We also demonstrated that SPARC was required for hydrogen peroxide (H₂O₂) production in fibroblasts treated with TGF-β. Furthermore, TGF-β activated integrin-linked kinase (ILK), which was inhibited by SPARC siRNA. Knockdown of ILK attenuated extracellular H₂O₂ generation in TGF-β-stimulated fibroblasts. Our results indicated that SPARC is upregulated by TGF-β and is required for TGF-β-induced H₂O₂ production via activation of ILK, and this H₂O₂ production from fibroblasts is capable of causing epithelial cell injury.

Conclusions

The results presented in this study suggest that SPARC plays a role in epithelial damage in the IPF lung via enhanced H₂O₂ production from fibroblasts activated by TGF-β. Therefore, SPARC inhibition may prevent epithelial injury in IPF lung and represent a potential therapeutic approach for IPF.

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Title: Secreted protein acidic and rich in cysteine (SPARC) is upregulated by transforming growth factor (TGF)-β and is required for TGF-β-induced hydrogen peroxide production in fibroblasts
Authors: Saiko Shibata
Junichi Ishiyama
Publication date: 01-12-2013
Publisher: BioMed Central
Published in: Fibrogenesis & Tissue Repair / Issue 1/2013
Electronic ISSN: 1755-1536
DOI: https://doi.org/10.1186/1755-1536-6-6

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