Resveratrol inhibits TGF-β1–induced fibrotic effects in human pterygium fibroblasts

Abstract

Background Resveratrol is a polyphenolic phytoalexin which has the properties of anti-oxidant, anti-inflammatory and anti-fibrotic effects. The aim of this study was to investigate the anti-fibrotic effects of resveratrol in primary human pterygium fibroblasts (HPFs) and elucidate the underlying mechanisms. Method Profibrotic activation was induced by transforming growth factor-beta1 (TGF-β1). The expression of profibrotic markers, including type 1 collagen (COL1), α-smooth muscle actin (α-SMA), and fibronectin, were detected by western blot and quantitative real-time-PCR after treatment with various concentrations of resveratrol in HPFs to investigate the anti-fibrotic effects. Relative signaling pathways downstream of TGF-β1 were detected by Western blot to assess the underlying mechanism. Cell viability and apoptosis were assessed using CCK-8 assay and flow cytometry to evaluate proliferation and drug-induced cytotoxicity. Cell migration and contractile phenotype were detected through wound healing assay and collagen gel contraction assay. Results The expression of α-SMA, FN and COL1 induced by TGF-β1 were suppressed by treatment with resveratrol in dose-dependent manner. The Smad3, mitogen-activated protein kinase (p38 MAPK) and phosphatidylinositol-3-kinase (PI3K) / protein kinase B (AKT) pathways were activated by TGF-β1, while resveratrol attenuated those pathways. Resveratrol also inhibited cellular proliferation, migration and contractile phenotype, and induced apoptosis in HPFs. Conclusions Resveratrol inhibit TGF-β1-induced myofibroblast activation and extra cellular matrix synthesis in HPFs, at least partly, by regulating the TGF-β/Smad3, p38 MAPK and PI3K/AKT pathways.

Potential of Plant-Derived Compounds in Preventing and Reversing Organ Fibrosis and the Underlying Mechanisms

“…Numerous in vitro and in vivo studies have highlighted the ability of resveratrol to attenuate fibrosis via inhibition of the canonical (Smad 2/3) and non-canonical TGF-β signaling pathways [ 92 , 93 , 94 , 95 , 96 ]. An investigation conducted on rat lung tissue revealed that the introduction of resveratrol led to a significant downregulation in the protein and RNA expression of TGF-β1, α-SMA, Smad3/4, p-Smad3/4, CTGF, collagen and p-ERK1/2 [ 93 ].…”

“…Guo et al described the cardiovascular protective effects of resveratrol, primarily attributed to its modulation of the non-canonical TGF-β/ERK1/2 signaling pathway [ 95 ]. Resveratrol treatment of isolated pterygium fibroblasts inhibited TGF-β1-induced proliferation, migration, contractility and expression of α-SMA, fibronectin and collagen type I [ 92 ]. Resveratrol treatment attenuated the activation of non-canonical p38 MAPK and PI3K/Akt pathways in these studies.…”