解毒化瘀通腑颗粒治疗亚急性和慢加急性肝衰竭患者的疗效及其对TLR4/NF-κB炎性通路的影响
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摘要
目的:评价解毒化瘀通腑颗粒对亚急性和慢加急性肝衰竭(SALF及ACLF)患者的治疗效果,并观察该方对TLR4/NF-κB炎性通路的影响。方法:将68例SALF及ACLF患者按随机数字表法随机分为两组,其中对照组患者给予常规内科综合支持治疗,试验组患者在对照组基础上加用解毒化瘀通腑颗粒。结果:治疗后试验组患者治疗总有效率明显高于对照组,差异有统计学意义(P <0. 05);与治疗前相比,两组患者肝功能相关指标、凝血酶原活动疫(PTA)、血浆内毒素(ET)均明显改善(P <0. 05),且试验组患者在血清总胆红素(TBil)、血清直接胆红素(DBil)、PTA、ET指标改善方面明显优于对照组(P <0. 05);而两组患者的血清胆碱酯酶(Che)、白蛋白(Alb)、谷氨酸氨基转移酶(ALT)、天门冬氨酸氨基转移酶(AST)、碱性磷酸酶(ALP)、谷氨酰转肽酶(GGT)水平方面,差异无统计学意义(P> 0. 05);治疗后两组患者的肿癌坏死因子-α(TNF-α)、白细胞介素-6(IL-6)均降低,且试验组均明显低于对照组,差异具有统计学意义(P <0. 05);治疗后两组患者的TLR4mRNA及NF-κBm RNA的表达较治疗前均降低,且试验组明显低于对照组,差异具有统计学意义(P <0. 05)。结论:解毒化瘀通腑颗粒可减轻SALF及ACLF患者临床症状,改善肝脏胆汁淤积状态,减轻肝损伤。其作用机制可能是通过促进患者内毒素的排泄或者抑制其吸收,减少内毒素的肝脏毒性反应,减轻肝损伤;并通过降低血清内毒素水平,影响患者TLR4/NF-κB信号通路,减少TNF-a、IL-6等相关炎性因子的产生及释放,达到减轻肝损伤的目的。
Objective: To evaluate the therapeutic effect of Jiedu Huayu Tongfu Granule on subacute and slowly acute hepatic failure.Methods: Sixty-eight cases who were diagnosed as subacute or acute on chronic liver failure patients were divided into 2 groups randomly,the control group received routine comprehensive support treatment,the experimental group was given Jiedu Huayu Tongfu granuleson on the basis of the control group. Results: After treatment,the total effective rate of experimental group was significantly higher than the control group,the difference was statistically significant(P < 0. 05); compared with before treatment,the related indicator of liver function,PTA and ET of 2 groups were significantly improved(P < 0. 05),and in the experimental group,TBIL,DBIL,PTA,ET index improved significantly better than the control group(P < 0. 05),while,there was no statistically significant between the two groups about the improvement of CHE,ALB,ALT,AST,ALP GGT(P > 0. 05). The TNF-α、IL-6 of the two groups were both decreased,and the experimental group was significantly lower than the control group(P < 0. 05); After treatment,the expression of TLR4 mRNA、NF-κBm RNA was lower than before treatment,and the experimental group was significantly lower than the control group(P < 0. 05). Conclusion: Jiedu Huayu Tongfu decoction can improve the clinical symptoms of SALF&ACLF patients,improve the metabolism and synthesis function of liver; Jiedu Huayu Tongfu prescription may promote excretion or inhibit the absorption of SALF&ACLF of endotoxin,reduce the liver toxicity from endotoxin,improve liver injury; Jiedu Huayu Tongfu may impact the TLR4/NF-κB signaling pathway by lowering the serum endotoxin level of the patients,to reduce the release of inflammatory cytokines such as TNF-a,IL-6 and cut down the damage of liver cells,and to treat SALF&ACLF.
Objective: To evaluate the therapeutic effect of Jiedu Huayu Tongfu Granule on subacute and slowly acute hepatic failure.Methods: Sixty-eight cases who were diagnosed as subacute or acute on chronic liver failure patients were divided into 2 groups randomly,the control group received routine comprehensive support treatment,the experimental group was given Jiedu Huayu Tongfu granuleson on the basis of the control group. Results: After treatment,the total effective rate of experimental group was significantly higher than the control group,the difference was statistically significant(P < 0. 05); compared with before treatment,the related indicator of liver function,PTA and ET of 2 groups were significantly improved(P < 0. 05),and in the experimental group,TBIL,DBIL,PTA,ET index improved significantly better than the control group(P < 0. 05),while,there was no statistically significant between the two groups about the improvement of CHE,ALB,ALT,AST,ALP GGT(P > 0. 05). The TNF-α、IL-6 of the two groups were both decreased,and the experimental group was significantly lower than the control group(P < 0. 05); After treatment,the expression of TLR4 mRNA、NF-κBm RNA was lower than before treatment,and the experimental group was significantly lower than the control group(P < 0. 05). Conclusion: Jiedu Huayu Tongfu decoction can improve the clinical symptoms of SALF&ACLF patients,improve the metabolism and synthesis function of liver; Jiedu Huayu Tongfu prescription may promote excretion or inhibit the absorption of SALF&ACLF of endotoxin,reduce the liver toxicity from endotoxin,improve liver injury; Jiedu Huayu Tongfu may impact the TLR4/NF-κB signaling pathway by lowering the serum endotoxin level of the patients,to reduce the release of inflammatory cytokines such as TNF-a,IL-6 and cut down the damage of liver cells,and to treat SALF&ACLF.
引文
[1]李梦东,聂青和.肝衰竭的研究现状与展望[J].实用肝脏病杂志,2013,16(1):9-11.
[2] Kitazawa T,Tsujimoto T,Kawaratani H,et al. Salvage effect of E5564,Toll-like receptor 4 antagonist on d-galactosamine and lipopoly saccharide-induced acute liver failure in rats[J]. Gastroenterol Hepatol,2010,25(5):1009-1012.
[3] Andrea B,Monica B,Gabriele V,et al. Inhibition of Toll-like receptor 4(TLR4)-induced NF-κB activation by NOPr is lost in human glioblastoma cells chronically exposed to LPS[J]. Brain Behav Immun,2013,29(Suppl):S18.
[4]陈斌.中医药治疗慢性重型肝炎的经验与进展[D].中华中医药学会第十五届内科肝胆病学术会议论文汇编,2012:3-5.
[5]中华医学会感染病学分会肝衰竭与人工肝学组,中华医学会肝病学分会重型肝病与人工肝学组.肝衰竭诊治指南(2012年版)[J].实用肝脏病杂志,2013,16(03):210-216.
[6] Nolan JP. The role of intestinal endotoxin in liver injury:a long and evolving history[J]. Hepatology,2010,52(5):1829-1835.
[7]王波,宋怀宇,杨建荣,等.肝病患者肠道屏障功能变化的研究进展[J].临床肝胆杂志,2011,27(8):893-896.
[8] Lee S,Son SC,Han MJ,et al. Increased intestinal macromolecular permeability and urine nit-rite excretion associated with liver cirrhosis with ascite[J]. World J Gastroenterol,2008,14(24):3884-3890.
[9] Verbeke L,Nevens F,Laleman W. Bench-to-beside review:Acute-onchronic liver failure linking the gut,liver and systemic circulation[J].Critical Care,2011,15(5):233-243.
[10] soares J B,Pimentel-Nunes P,Roncon-A1buquerque R,et a1. The role of 1ipopolysaccharide/toll-like receptor 4 signaling in chronic liver diseases[J]. Hepatol Int,2010,4(4):659-662.
[11]赵军,刘旭华,陈煜.内毒素性肝衰竭大鼠TLR4mRNA表达、血清肿瘤坏死因子-α及肝细胞凋亡的动态变化[J].胃肠病学和肝病学杂志,2008,17(1):42-45.
[12] Lu Y C,Yeh W C,Ohashi P S. LPS/TLR4 signal transduction pathway[J].Cytokine,2008,42(2):145-151.
[13] Ohuchida K,Mizumoto K,Lin C,et al. Micro RNA-10a is overexpressed in human pancreatic cancer and involved in its invasiveness partially via suppression of the HOXA1 gene[J]. Ann Surg Oncol,2012,19(7):2394-2402.
[14] Ishizuka F,Shimazawa M,Inoue Y,et al. Toll-like receptor 4 mediates retinal ischemia/reperfusion injury through nuclear factor kappaB and spleen tyrosine kinase activation[J]. Invest Ophthalmol Vis Sci,2013,54(8):5807-5816.
[15]熊焰.温阳解毒化瘀法对肝衰竭IETM非阳黄证的干预机制及临床疗效研究[D].湖南中医药大学,2014.
[16]李金科,李云静,谢杏榕,等.肝康Ⅱ号对重型肝炎内毒素血症的影响[J].中国肝脏病杂志(电子版),2014,16(2):53-55.
[17]马文峰,周小舟,孙新锋,等.生脉散调节大鼠慢性肝衰竭内毒素血症的机理研究[J].中医临床研究,2013,21(3):8-10.
[18]张雪,袁惠芳.肝病内毒素血症中医辨治初探[J].浙江中医杂志,2007,42(1):18-20.
[19]李筠.内毒素在肝衰竭形成中的作用及中医药治疗[J].传染病信息,2010,23(5):260-262.
[20]汪承柏.重视慢性肝炎内毒素血症的防治[J].中西医结合肝病杂志,2001,11(4):193-194.
[21]张友祥,周新喜,徐庆年,等.肝硬化肠源性内毒素血症中医辨证分型及相关因素的初步探讨[J].中西医结合肝病杂志,2010,20(2):77-79.
[22]张照兰,郭胜,郭勇义.退黄合剂对ANIT诱发肝内胆汁淤积大鼠的影响[J].中国中医药信息杂志,2004,11(12):1052-1053.
[23]马素平.退黄合剂治疗黄疸型病毒性肝炎56例[J].陕西中医,2006,27(1):18-19.
[24]刘光伟,费景兰,王春芳,等.退黄合剂口服及保留灌肠联合大剂量丹参注射液治疗重型肝炎临床疗效观察[J].中国中西医结合急救杂志,2011,18(4):206-208.
[2] Kitazawa T,Tsujimoto T,Kawaratani H,et al. Salvage effect of E5564,Toll-like receptor 4 antagonist on d-galactosamine and lipopoly saccharide-induced acute liver failure in rats[J]. Gastroenterol Hepatol,2010,25(5):1009-1012.
[3] Andrea B,Monica B,Gabriele V,et al. Inhibition of Toll-like receptor 4(TLR4)-induced NF-κB activation by NOPr is lost in human glioblastoma cells chronically exposed to LPS[J]. Brain Behav Immun,2013,29(Suppl):S18.
[4]陈斌.中医药治疗慢性重型肝炎的经验与进展[D].中华中医药学会第十五届内科肝胆病学术会议论文汇编,2012:3-5.
[5]中华医学会感染病学分会肝衰竭与人工肝学组,中华医学会肝病学分会重型肝病与人工肝学组.肝衰竭诊治指南(2012年版)[J].实用肝脏病杂志,2013,16(03):210-216.
[6] Nolan JP. The role of intestinal endotoxin in liver injury:a long and evolving history[J]. Hepatology,2010,52(5):1829-1835.
[7]王波,宋怀宇,杨建荣,等.肝病患者肠道屏障功能变化的研究进展[J].临床肝胆杂志,2011,27(8):893-896.
[8] Lee S,Son SC,Han MJ,et al. Increased intestinal macromolecular permeability and urine nit-rite excretion associated with liver cirrhosis with ascite[J]. World J Gastroenterol,2008,14(24):3884-3890.
[9] Verbeke L,Nevens F,Laleman W. Bench-to-beside review:Acute-onchronic liver failure linking the gut,liver and systemic circulation[J].Critical Care,2011,15(5):233-243.
[10] soares J B,Pimentel-Nunes P,Roncon-A1buquerque R,et a1. The role of 1ipopolysaccharide/toll-like receptor 4 signaling in chronic liver diseases[J]. Hepatol Int,2010,4(4):659-662.
[11]赵军,刘旭华,陈煜.内毒素性肝衰竭大鼠TLR4mRNA表达、血清肿瘤坏死因子-α及肝细胞凋亡的动态变化[J].胃肠病学和肝病学杂志,2008,17(1):42-45.
[12] Lu Y C,Yeh W C,Ohashi P S. LPS/TLR4 signal transduction pathway[J].Cytokine,2008,42(2):145-151.
[13] Ohuchida K,Mizumoto K,Lin C,et al. Micro RNA-10a is overexpressed in human pancreatic cancer and involved in its invasiveness partially via suppression of the HOXA1 gene[J]. Ann Surg Oncol,2012,19(7):2394-2402.
[14] Ishizuka F,Shimazawa M,Inoue Y,et al. Toll-like receptor 4 mediates retinal ischemia/reperfusion injury through nuclear factor kappaB and spleen tyrosine kinase activation[J]. Invest Ophthalmol Vis Sci,2013,54(8):5807-5816.
[15]熊焰.温阳解毒化瘀法对肝衰竭IETM非阳黄证的干预机制及临床疗效研究[D].湖南中医药大学,2014.
[16]李金科,李云静,谢杏榕,等.肝康Ⅱ号对重型肝炎内毒素血症的影响[J].中国肝脏病杂志(电子版),2014,16(2):53-55.
[17]马文峰,周小舟,孙新锋,等.生脉散调节大鼠慢性肝衰竭内毒素血症的机理研究[J].中医临床研究,2013,21(3):8-10.
[18]张雪,袁惠芳.肝病内毒素血症中医辨治初探[J].浙江中医杂志,2007,42(1):18-20.
[19]李筠.内毒素在肝衰竭形成中的作用及中医药治疗[J].传染病信息,2010,23(5):260-262.
[20]汪承柏.重视慢性肝炎内毒素血症的防治[J].中西医结合肝病杂志,2001,11(4):193-194.
[21]张友祥,周新喜,徐庆年,等.肝硬化肠源性内毒素血症中医辨证分型及相关因素的初步探讨[J].中西医结合肝病杂志,2010,20(2):77-79.
[22]张照兰,郭胜,郭勇义.退黄合剂对ANIT诱发肝内胆汁淤积大鼠的影响[J].中国中医药信息杂志,2004,11(12):1052-1053.
[23]马素平.退黄合剂治疗黄疸型病毒性肝炎56例[J].陕西中医,2006,27(1):18-19.
[24]刘光伟,费景兰,王春芳,等.退黄合剂口服及保留灌肠联合大剂量丹参注射液治疗重型肝炎临床疗效观察[J].中国中西医结合急救杂志,2011,18(4):206-208.