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

Abstract

BackgroundIdiopathic 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.ResultsAmong 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.ConclusionsThe 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.

Scarring vs. functional healing: Matrix-based strategies to regulate tissue repair

“…SPARC-deficient mice exhibit tissue repair defects manifesting as delayed formation of granulation tissue and diminished ECM production [46]. SPARC is also involved in idiopathic pulmonary fibrosis through activation by TGFβ [47]. Inhibition of SPARC attenuates the pro-fibrotic effect of TGFβ [48].…”

Matricellular Proteins and Organ Fibrosis

“…Sangaletti et al proposed a differential function of SPARC in fibroblasts and macrophages in a model of bleomycininduced lung fibrosis; using SPARC depleted mice and bone marrow chimeras, they found that SPARC expression by fibroblasts was required to induce collagen deposition, while SPARC depletion from macrophages caused exacerbated inflammation and fibrosis because of their inability to downregulate TNF-a production (92). In another study, SPARC was required for H2O2 production by lung fibroblasts after TGF-β1 treatment, while SPARC knock-down in fibroblasts attenuated epithelial cell injury in a co-culture system (93). In liver fibrosis SPARC is upregulated in activated HSCs and mediates their migration towards TGF-β1 and TGF-β1 secretion (94).…”

SPARC acts as a mediator of TGF‐β1 in promoting epithelial‐to‐mesenchymal transition in A549 and H1299 lung cancer cells

“…Many articles reported that SPARC acted as a regulator of cancer cell metastasis and carcinogenesis . In fibroblasts, SPARC was upregulated by TGF‐β1 and required for hydrogen peroxide production . SPARC was overexpressed in idiopathic pulmonary fibrosis fibroblasts and conferred an apoptosis‐resistant phenotype .…”