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腺苷酸活化蛋白激酶(AMP activated protein kinase,AMPK)是重要的代谢调节酶及炎症调控新靶点。以往研究显示,AMPK激活剂5-氨基咪唑-4-甲酰胺核苷酸转甲酰酶(5-amino-4-imidazolecarboxamide riboside,AICAR)可通过抑制炎症反应减轻脂多糖/右旋半乳糖胺(lipopolysaccharide/D-galactosamine,LPS/D-gal)诱导的爆发性肝炎。由于炎症可通过激活凝血反应加重组织损伤,本研究旨在以炎症诱导凝血反应为切入点探讨AICAR保肝效应的机制。腹腔注射LPS/D-gal建立爆发性肝炎小鼠模型,用Western blot检测肝内组织因子(tissue factor,TF)、缺氧诱导因子1-α(hypoxia-inducible factor 1α,HIF-1α)以及细胞核内核因子kappa B(nuclear factor kappa B,NF-κB)p65蛋白表达,用实时定量PCR检测肝细胞促红细胞生成素(erythropoietin,EPO)m RNA表达,用试剂盒检测肝组织乳酸(lactic acid,LA)水平。结果显示,LPS/D-gal可促进小鼠肝细胞内TF蛋白表达,提高细胞核内NF-κB p65水平,上调HIF-1α蛋白及EPO m RNA表达,并提高肝组织LA水平;而AICAR干预后,以上指标均明显下调。以上结果提示,AICAR可通过抑制NF-κB活性下调TF表达及凝血活性,从而减轻肝组织缺氧及代谢紊乱,这可能是AICAR减轻LPS/D-gal诱导的爆发性肝炎的新机制。
AMP activated protein kinase (AMP) is an important metabolic regulator and a new target of inflammation regulation. Previous studies have shown that the AMPK activator 5-amino-4-imidazolecarboxamide riboside (AICAR) can reduce lipopolysaccharide / D-galactosamine by inhibiting inflammatory reaction lipopolysaccharide / D-galactosamine, LPS / D-gal) induced fulminant hepatitis. As inflammation can aggravate tissue damage by activating coagulation, the aim of this study was to investigate the mechanism of AICAR hepatoprotective effect with the inflammatory induction of coagulation as the starting point. The mouse model of fulminant hepatitis was established by intraperitoneal injection of LPS / D-gal and the expression of tissue factor (TF), hypoxia-inducible factor 1α (HIF-1α) and nuclear The expression of nuclear factor kappa B (NF-κB) p65 protein was detected by real-time quantitative PCR. Expression of erythropoietin mRNA was detected by real-time PCR. The expression of lactic acid (LA) )Level. The results showed that LPS / D-gal could promote TF protein expression in liver cells, increase the level of NF-κB p65 in the nucleus, up-regulate the expression of HIF-1α protein and EPO m RNA, and increase the level of LA in liver tissue. , The above indicators were significantly reduced. The above results suggest that AICAR can down-regulate the expression of TF and coagulation activity by inhibiting the activity of NF-κB, thereby reducing the hypoxia and metabolic disturbance in liver tissue, which may be a new mechanism of AICAR in reducing LPS / D-gal-induced fulminant hepatitis.