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首页> 外文期刊>Cellular Physiology and Biochemistry >Reduced hepatic injury in toll-like receptor 4-deficient mice following D-galactosamine/lipopolysaccharide-induced fulminant hepatic failure
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Reduced hepatic injury in toll-like receptor 4-deficient mice following D-galactosamine/lipopolysaccharide-induced fulminant hepatic failure

机译：减少D-半乳糖胺/脂多糖诱导的暴发性肝衰竭后Toll样受体4缺陷小鼠的肝损伤

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摘要

Liver transplantation is the only therapy of proven benefit in fulminant hepatic failure (FHF). Lipopolysaccharide (LPS), D-galactosamine (GalN)-induced FHF is a well established model of liver injury in mice. Toll-Like Receptor 4 (TLR4) has been identified as a receptor for LPS. The aim of this study was to investigate the role of TLR4 in FHF induced by D-GalN/LPS administration in mice. Wild type (WT) and TLR4 deficient (TLR4ko) mice were studied in vivo in a fulminant model induced by GalN/LPS. Hepatic TLR4 expression, serum liver enzymes, hepatic and serum TNF-α and interleukin-1β levels were determined. Apoptotic cells were identified by immunohistochemistry for caspase-3. Nuclear factor-kappaβ (NF-κ β) and phosphorylated c-Jun hepatic expression were studied using Western blot analysis. All WT mice died within 24 hours after administration of GalN/LPS while all TLR4ko mice survived. Serum liver enzymes, interleukin-1β, TNF-α level, TLR4 mRNA expression, hepatic injury and hepatocyte apoptosis all significantly decreased in TLR4ko mice compared with WT mice. A significant decrease in hepatic c-Jun and IκB signaling pathway was noted in TLR4ko mice compared with WT mice. In conclusion, following induction of FHF, the inflammatory response and the liver injury in TLR4ko mice was significantly attenuated through decreased hepatic c-Jun and NF-κB expression and thus decreased TNF-α level. Down-regulation of TLR4 expression plays a pivotal role in GalN/LPS induced FHF. These findings might have important implications for the use of the anti TLR4 protein signaling as a potential target for therapeutic intervention in FHF.
机译：肝移植是证明对暴发性肝衰竭（FHF）有益处的唯一疗法。脂多糖（LPS），D-半乳糖胺（GalN）诱导的FHF是小鼠肝损伤的公认模型。 Toll-like受体4（TLR4）已被确定为LPS的受体。这项研究的目的是调查TLR4在D-GalN / LPS给予小鼠诱导的FHF中的作用。在GalN / LPS诱导的暴发模型中体内研究了野生型（WT）和TLR4缺陷（TLR4ko）小鼠。测定肝TLR4表达，血清肝酶，肝和血清TNF-α和白介素-1β水平。通过免疫组织化学对caspase-3鉴定凋亡细胞。使用蛋白质印迹分析研究了核因子-κβ（NF-κβ）和磷酸化的c-Jun肝表达。在施用GalN / LPS后24小时内，所有WT小鼠死亡，而所有TLR4ko小鼠均存活。与野生型小鼠相比，TLR4ko小鼠的血清肝酶，白介素-1β，TNF-α水平，TLR4 mRNA表达，肝损伤和肝细胞凋亡均明显降低。与野生型小鼠相比，TLR4ko小鼠的肝c-Jun和IκB信号通路显着降低。总之，在诱导FHF之后，TLR4ko小鼠的炎症反应和肝损伤通过降低肝脏c-Jun和NF-κB表达而显着减弱，从而降低TNF-α水平。 TLR4表达的下调在GalN / LPS诱导的FHF中起关键作用。这些发现对于将抗TLR4蛋白信号传导用作FHF治疗干预的潜在靶标可能具有重要意义。

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