stilbenes and Airway-Remodeling

Reactive oxygen species (ROS) and epithelial-mesenchymal transition (EMT) play a critical role in transforming growth factor (TGF)-β1-mediated fibrotic airway remodeling in asthma. Polydatin (PD) is a small natural molecule in Chinese medicine; it is isolated from Polygonum cuspidatum and has antioxidative properties. In this study, we aimed to determine whether PD was protective against ROS-induced pulmonary fibrosis in asthma. Ovalbumin (OVA) was used to induce asthma in a mouse model that was treated with or without PD. We also created nuclear factor erythroid 2-related factor 2 (Nrf2) knockdown BEAS-2B cells and investigated whether PD reversed TGF-β1-induced pulmonary epithelial cell EMT by promotion of Nrf2-mediated antioxidation. Immunofluorescence showed that ROS and TGF-β1 expression was significantly increased in lung tissue from the OVA-induced asthma model. PD treatment inhibited activity of ROS and TGF-β1. Immunohistochemistry showed that PD treatment decreased OVA-induced lung ROS, TGF-β1 expression and fibroblasts. Western blotting showed that PD treatment reversed OVA-induced NADPH oxidase (NOX)1/4 expression by promoting Nrf2-mediated heme oxygenase-1 and NADPH dehydrogenase (quinone)-1 expression. PD treatment suppressed OVA-induced EMT and lung fibroblast protein expression in lung tissue. Nrf2 downregulation suppressed the protective effect of PD by promoting TGF-β1-induced ROS and EMT and accumulation of extracellular-matrix-related protein. All these data indicate that PD has potential therapeutic effects in asthma by promoting Nrf2-mediated antioxidation.

Topics: Airway Remodeling; Animals; Antioxidants; Asthma; Cells, Cultured; Disease Models, Animal; Epithelial Cells; Epithelial-Mesenchymal Transition; Glucosides; Humans; Lung; Male; Mice; Mice, Inbred BALB C; Mice, Nude; NF-E2-Related Factor 2; Ovalbumin; Reactive Oxygen Species; Signal Transduction; Stilbenes; Transforming Growth Factor beta1

Resveratrol, a natural polyphenolic compound known for its antioxidative and antiinflammatory effects, exerts antiasthmatic effects, although the mechanism underlying these effects remains elusive. The phosphatase and tensin homology deleted on chromosome ten gene (PTEN) is involved in the pathogenesis of asthma, and PTEN overexpression in asthmatic mice improved asthma symptoms. To investigate whether the antiasthmatic mechanisms of resveratrol correlated with the upregulation of PTEN expression, an ovalbumin (OVA)-induced murine asthma model was used to determine the effectiveness of resveratrol treatment. PTEN mRNA and protein expression was assessed with real-time polymerase chain reaction (PCR) and immunochemistry. To determine whether airway remodeling occurred, the inner airway wall, mucous layer, and smooth muscle areas were each determined using an image analysis system. The lung epithelial cell line 16HBE was used to study the regulation of PTEN expression levels by resveratrol in vitro. Our data demonstrated that resveratrol inhibited OVA-induced airway inflammation and airway remodeling in asthmatic mice. PTEN expression was decreased in the murine asthma model, although the expression of PTEN was restored following treatment with resveratrol. Correlation efficiency analysis showed that PTEN expression was associated with the degree of airway remodeling. Further in vitro studies demonstrated that the inhibition of Sirtuin 1 (SIRT1) activity by a SIRT1 inhibitor and RNA interference decreased PTEN protein expression, while resveratrol attenuated the decreases in PTEN expression induced by the SIRT1 inhibitor. These data suggest the mechanism of the antiasthmatic effects of resveratrol in an OVA-induced murine asthma model, which resulted in the upregulation of PTEN via SIRT1 activation.

Topics: Airway Remodeling; Animals; Anti-Asthmatic Agents; Asthma; Cell Line; Disease Models, Animal; Female; Humans; Lung; Mice, Inbred BALB C; Ovalbumin; PTEN Phosphohydrolase; Resveratrol; Sirtuin 1; Stilbenes; Up-Regulation

This study has two novel findings: it is not only the first to demonstrate inflammatory cytokines, which are produced by the bronchial epithelium after exposure to benzo[a]pyrene (BaP) and contribute to airway remodeling by increasing human bronchial smooth muscle cells (BSMC) proliferation and migration, but also the first to reveal that pterostilbene, a constituent of grapes and berries, reverses BaP-mediated airway remodeling. Human bronchial epithelial cell lines BEAS-2B and HBE135-E6E7 (HBE) were treated with BaP, and then the condition medium (CM) was harvested, which was then added to BSMC. Cultures of BSMC with BaP-BEAS-2B-CM and -HBE-CM increased BSMC proliferation and migration, which are major features in asthma remodeling. Exposure of BEAS-2B and HBE to BaP caused epithelial cells to produce inflammatory cytokines IL-8, which subsequently induced BSMC proliferation and migration. Moreover, pterostilbene is more potent than resveratrol in suppressing BaP-mediated airway remodeling. This study suggests that pterostilbene is capable of preventing BaP-associated asthma.

Topics: Airway Remodeling; Benzo(a)pyrene; Bronchi; Cell Line; Cell Proliferation; Down-Regulation; Humans; Myocytes, Smooth Muscle; Stilbenes