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首页> 外文期刊>Toxicology Letters: An International Journal Providing a Forum for Original and Pertinent Contributions in Toxicology Research >2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) induces hepatic stellate cell (HSC) activation and liver fibrosis in C57BL6 mouse via activating Akt and NF-kappa B signaling pathways
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2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) induces hepatic stellate cell (HSC) activation and liver fibrosis in C57BL6 mouse via activating Akt and NF-kappa B signaling pathways

机译：2,3,7,8-四氯二苯并二苯苯并二恶蛋白（TCDD）通过激活AKT和NF-Kappa发信号通路在C57BL6小鼠中诱导肝星状细胞（HSC）活化和肝纤维化

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2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a widespread environmental pollutant that could induce serious toxic effects in both humans and rodents. Some studies suggested that TCDD exposure may facilitate the activation of hepatic stellate cells (HSCs) and liver injury. However, the underlying molecular mechanism by which environmental pollutants promote liver injury remains poorly understood. In the present study, we established an animal model of TCDD exposure by intraperitoneal injection of TCDD in male C57BL/6J mice. As revealed by Sirius red staining and hematoxylin-eosin (H&E) staining evaluation, we found that TCDD-exposed mice showed extensive disruption of liver architecture, including hepatocellular necrosis, inflammatory cell infiltration, and fibrosis. Furthermore, we showed that TCDD up-regulated the expression and secretion of the pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) in a dose-dependent manner in cultured HSCs. The effects of TCDD on cytokine secretion were very likely mediated by protein kinase B/Akt and Nuclear Factor kappa B (NF-kappa B) pathways, as indicated by the fact that TCDD markedly increased Akt phosphorylation and nuclear translocation of NF-kappa B p65 in HSCs. Furthermore, LY294002, an Akt inhibitor, significantly attenuated TCDD-triggered HSC activation through blocking Akt phosphorylation and NF- kappa B activation. These results indicate that HSCs are susceptible to the cytotoxic effects of TCDD and chronic TCDD exposure may contribute to liver fibrosis by activating HSC Akt and NF-kappa B signaling pathways. (C) 2017 Elsevier B.V. All rights reserved.
机译：2,3,7,8-四氯二苯并苯并-P-二恶英（TCDD）是一种广泛的环境污染物，可在人类和啮齿动物中引起严重的毒性作用。一些研究表明，TCDD暴露可以促进肝星状细胞（HSC）和肝损伤的激活。然而，环境污染物促进肝损伤的潜在分子机制仍然明白。在本研究中，我们通过腹腔注射TCDD在雄性C57BL / 6J小鼠中建立了TCDD暴露的动物模型。如天狼星红染色和苏木精 - 曙红（H＆E）染色评价，我们发现TCDD暴露的小鼠表现出广泛的肝脏结构中断，包括肝细胞坏死，炎症细胞浸润和纤维化。此外，我们表明，TCDD以培养的HSC在培养的HSC中以一种剂量依赖性方式调节促炎细胞因子肿瘤坏死因子-α（TNF-α）和白细胞介素-6（IL-6）的表达和分泌。 TCDD对细胞因子分泌的影响非常可能是由蛋白激酶B / Akt和核因子Kappa B（NF-Kappa B）途径介导的，如TCDD显着增加的AKT磷酸化和NF-Kappa B P65的核易位所示在HSC。此外，通过阻断AKT磷酸化和NF-Kappa B活化，Ly294002，AKT抑制剂，显着减弱了TCDD触发的HSC活化。这些结果表明，HSCs易患TCDD和慢性TCDD暴露的细胞毒性作用可能通过激活HSC AKT和NF-Kappa发信号通路来促进肝纤维化。 （c）2017 Elsevier B.v.保留所有权利。

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